Proteins and nucleic acids useful in vaccines targeting Klebsiella pneumoniae

ABSTRACT

The present invention relates to proteins and nucleic acids derived from Klebsiella pneumoniae as well as therapeutic and diagnostic uses of the proteins and nucleic acids.

CROSS REFERENCE TO RELATED APPLICATIONS

In accordance with 37 C.F.R. 1.76, a claim of priority is included in anApplication Data Sheet filed concurrently herewith. Accordingly, thepresent invention claims priority as a continuation of U.S. patentapplication Ser. No. 16/594,987, entitled “PROTEINS AND NUCLEIC ACIDSUSEFUL IN VACCINES TARGETING KLEBSIELLA PNEUMONIAE”, filed Oct. 7, 2019,which is a continuation of U.S. patent application Ser. No. 15/542,580,entitled “PROTEINS AND NUCLEIC ACIDS USEFUL IN VACCINES TARGETINGKLEBSIELLA PNEUMONIAE”, filed Jul. 10, 2017, now U.S. Pat. No.10,434,162, issued Oct. 8, 2019, which is a § 371 national stage entryof International Application No. PCT/EP2016/050468, entitled “PROTEINSAND NUCLEIC ACIDS USEFUL IN VACCINES TARGETING KLEBSIELLA PNEUMONIAE”,filed Jan. 12, 2016, which claims the benefit of the priority ofEuropean Patent Application No. 15150819.9, entitled “PROTEINS ANDNUCLEIC ACIDS USEFUL IN VACCINES TARGETING KLEBSIELLA PNEUMONIAE”, filedJan. 12, 2015, the entire contents of each are incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to the field of antimicrobial prophylaxisand therapy. In particular the present invention relates to novelproteins and polynucleotides derived from Klebsiella pneumoniae. Theinvention further relates to vectors comprising the polynucleotides,transformed host organisms expressing the polynucleotides, antibodies(mono- or polyclonal) specific for the polypeptides as well asdiagnostic, prophylactic and therapeutic uses and methods. Finally, alsomethods of preparation are part of the invention.

BACKGROUND OF THE INVENTION

Bacterial infections are in most instances successfully treated byadministration of antibiotics to patients in need thereof. However, dueto careless or thoughtless use of powerful antibiotics, manypathological germs become resistant against antibiotics over time. Onethreatening example is Klebsiella pneumoniae.

The genus Klebsiella belongs to the family Enterobacteriaceae and isdivided into at least 4 species. They are gram-negative, capsulated,oxidase-negative, non-motile, straight rods. They are facultativeanaerobes, having both a respiratory and fermentative metabolism. Moststrains can use citrate and glucose as their sole carbon source. Somestrains can fix nitrogen. They are commonly found in the intestines,clinical samples, soil, water and grains. The species Klebsiellapneumoniae can be divided into 3 subspecies; pneumoniae, ozaenae andrhinoscleromatis (Orskov, I. 1984. Genus V. Klebsiella Trevisan 1885,105.

Krieg and Holt (editors) In Bergey's Manual of Systematic Bacteriology,1:461-465). Klebsiella pneumoniae is the most common gram-negativepathogen causing community acquired pneumonia (Carpenter, J., et al,1990. Rev Infect. Dis. 12:672-682). Klebsiella is also responsible foran estimated 8% of all nosocomial infections (Sahly, H. and Podschun,R., 1997. Clin. Diagn. Lab. Immunol. 4:393-399).

K. pneumoniae is an opportunistic pathogen that is associated withpneumonia, septicemia, meningitis, endocarditis, ventriculitis, andinfections of urinary tract and wounds. These diseases are bothnosocomial and community acquired. K. pneumoniae also plays a large rolein two major nonrheumatoid arthritic diseases, Ankylosing Spondylitisand Reiter's Syndrome (Schwimmbeck, P. and Oldstone, M., 1989. CurrentTopics in Microbiology and Immunology. 145:45-56.). Despite availableantibiotics, observed mortality rates for pneumonia are approximately50%, but when bacteremic K. pneumoniae occurs in alcoholics, themortality rises to almost 100% (Sahly, H. and Podschun, R., 1997. Clin.Diagn. Lab. Immunol. 4:393-399). The overall mortality rate forKlebsiella bacteremia in one study was 37% and has ranged in others from25% to 55% (Watanakunakron, C. and Jura, J., 1991. Scand. J. Infect.Dis. 23:399-405).

Incidence of K. pneumoniae meningitis is on the rise. A study of 3377cases of Bacterial meningitis in 1948, found only 7 were K. pneumoniae.In 1957, K. pneumonia accounted for 1.5% of all cases of meningitis. Inan eleven-year study, from 1981 to 1991, 13% of culture proven bacterialmeningitis cases were K. pneumoniae. There was an increase occurrence ofK. pneumoniae meningitis within this study with 7% occurrence in thefirst 6 years, and 16% occurrence in the last 5 years (Tang, L-M andChen, S-T., 1994. Scand. J. Infect. Dis. 26:95-102).

In recent years, Klebsiella strains have become multi-resistant to manyantibiotics. In the 1970's, the resistance was mainly to aminoglycosideantibiotics. Since 1982, some Klebsiella strains have become resistantto the extended-spectrum cephalosporins (Sahly, H. and Podschun, R.,1997. Clin. Diagn. Lab. Immunol. 4:393-399). Resistance to theextended-spectrum cephalosporins among clinical isolates of Klebsiellain France and England has been reported at 14 to 16% (Sirot, D. 1995 J.Antimicrob. Chemother. 36:19-34). Since Klebsiella is a good recipientfor R factors, resistance has been gained to β-lactams, tetracycline,chloramphenicols, ceftazidime, sulfonamides and trimethoprim. Today,almost all strains of Klebsiella are resistant to ampicillin. (Orskov,I. 1984. Genus V. Klebsiella Trevisan 1885, 105. Krieg and Holt(editors) In Bergey's Manual of Systematic Bacteriology, 1:461-465).

Microbial fermentation is an important way to convert renewableresources to products of biological and industrial importance. K.pneumoniae has been used to convert simple sugars to the commoditychemicals 1,3-propanediol and 1,2-propanediol. These products have beenmade by fed-batch fermentation of glycerol by K. pneumoniae. (Cameron,D. et al, 1998. Biotechnol. Prog. 14:116-125). Genes from the1,3-propanediol pathway of K. pneumoniae have recently been cloned andexpressed into both E. coli and S. cerevisiae. Metabolic engineering ofthese genes can significantly improve the product yield and productivity(Cameron, D. et al, 1998. Biotechnol. Prog. 14:116-125).

With K. pneumoniae playing the lead role, the Klebsiella genus isbecoming an increasingly important pathogen. Over the past 10 years,discovery of multi-drug resistant strains has emphasized the importanceof this genus. Furthermore, Klebsiella is considered to be a model forsystemic infections caused by capsulated bacteria.

Vaccination is considered to be a very effective method of preventinginfectious diseases in human and veterinary health care. Vaccination isthe administration of immungenically effective amounts of antigenicmaterial (the vaccine) to produce immunity to a disease/disease-causingpathogenic agent. Vaccines have contributed to the eradication ofsmallpox, the near eradication of polio, and the control of a variety ofdiseases, including rubella, measles, mumps, chickenpox, typhoid fever.

Before “the genomic era”, vaccines were based on killed or liveattenuated, microorganisms, or parts purified from them. Subunitvaccines are considered as a modern upgrade of these types of vaccine,as the subunit vaccines contain one or more protective antigens, whichare more or less the weak spot of the pathogen. Hence, in order todevelop subunit vaccines, it is critical to identify the proteins, whichare important for inducing protection and to eliminate others.

An antigen is said to be protective if it is able to induce protectionfrom subsequent challenge by a disease-causing infectious agent in anappropriate animal model following immunization.

The empirical approach to subunit vaccine development, which includesseveral steps, begins with pathogen cultivation, followed bypurification into components, and then testing of antigens forprotection. Apart from being time and labour consuming, this approachhas several limitations that can lead to failure. It is not possible todevelop vaccines using this approach for microorganisms, which cannoteasily be cultured and only allows for the identification of theantigens, which can be obtained in sufficient quantities. The empiricalapproach has a tendency to focus on the most abundant proteins, which insome cases are not immuno-protective. In other cases, the antigenexpressed during in vivo infection is not expressed during in vitrocultivation. Furthermore, antigen discovery by use of the empiricalapproach demands an extreme amount of proteins in order to discover theprotective antigens, which are like finding needles in the haystack.This renders it a very expensive approach, and it limits the vaccinedevelopment around diseases, which is caused by pathogens with a largegenome or disease areas, which perform badly in a cost-effectiveperspective.

OBJECT OF THE INVENTION

It is an object of embodiments of the invention to provide K. pneumoniaederived antigenic polypeptides that may serve as constituents invaccines against K. pneumoniae infections and in diagnosis of K.pneumoniae infections. It is also an object to provide nucleic acids,vectors, transformed cells, vaccine compositions, and other useful meansfor molecular cloning as well as for therapy and diagnosis withrelevance for K. pneumoniae.

SUMMARY OF THE INVENTION

It has been found by the present inventor(s) that K. pneumoniae, inparticular drug resistant K. pneumoniae, expresses a number of hithertounknown putatively surface exposed proteins which are candidates asvaccine targets as well as candidates as immunizing agents forpreparation of antibodies that target K. pneumoniae.

So, in a first aspect the present invention relates to a polypeptidecomprising

a) an amino acid sequence selected from the group consisting of any oneof SEQ ID NOs: 1-30, 93, and 94, or

b) an amino acid sequence consisting of at least or exactly or at most 5contiguous amino acid residues from any one of SEQ ID NOs: 1-30, 93, and94, or

c) an amino acid sequence having a sequence identity of at least 60%with the amino acid sequence of a),

d) an amino acid sequence having a sequence identity of at least 60%with the amino acid sequence of b), or

e) an assembly of amino acids derived from any one of SEQ ID NOs: 1-30,93, and 94, which has essentially the same 3D conformation as in theprotein from which said assembly is derived so as to constitute a B-cellepitope, said polypeptide being antigenic in a mammal.

In a second aspect, the invention relates to an isolated nucleic acidfragment, which comprises

i) a nucleotide sequence encoding a polypeptide of the invention, or

ii) a nucleotide sequence consisting of any one of SEQ ID NOs: 31-90 and95-102.

iii) a nucleotide sequence consisting of at least or exactly or at most10 consecutive nucleotides in any one of SEQ ID NOs: 31-90 and 95-102,

iv) a nucleotide sequence having a sequence identity of at least 60%with the nucleotide sequence in i) or ii),

v) a nucleotide sequence having a sequence identity of at least 60% withthe nucleotide sequence in iii),

vi) a nucleotide sequence complementary to the nucleotide sequence ini)-v), or

vii) a nucleotide sequence which hybridizes under stringent conditionswith the nucleotide sequence in i)-vi).

In a third aspect, the invention relates to a vector comprising thenucleic acid of the invention, such as a cloning vector or an expressionvector.

In fourth aspect, the invention relates to a cell which is transformedso as to carry the vector of the invention.

In a fifth aspect, the invention relates to a pharmaceutical compositioncomprising a polypeptide of the invention, a nucleic acid fragment ofthe invention, a vector of the invention, or a transformed cell of theinvention, and a pharmaceutically acceptable carrier, vehicle ordiluent.

In a sixth aspect, the invention relates to a method for inducingimmunity in an animal by administering at least once an immunogenicallyeffective amount of a polypeptide of the invention, a nucleic acidfragment of the invention, a vector of the invention, a transformed cellof the invention, or a pharmaceutical composition of the fifth aspect ofthe invention so as to induce adaptive immunity against K. pneumoniae inthe animal.

In a seventh and eighth aspect, the invention relates to 1) a polyclonalantibody in which the antibodies specifically bind to at least onepolypeptide of the invention, and which is essentially free fromantibodies binding specifically to other K. pneumoniae polypeptides, andto 2) an isolated monoclonal antibody or antibody analogue which bindsspecifically to a polypeptide of the invention. In a related ninthaspect, the invention relates to a pharmaceutical composition comprisingsuch a polyclonal or monoclonal antibody and a pharmaceuticallyacceptable carrier, vehicle or diluent.

In a 10^(th) aspect, the invention relates to a method for prophylaxis,treatment or amelioration of infection with K. pneumoniae, comprisingadministering a therapeutically effective amount of an antibody of the7^(th) or 8^(th) aspect of the invention or a pharmaceutical compositionof the eighth aspect to an individual in need thereof.

In an 11^(th) aspect, the invention relates to a method for determining,quantitatively or qualitatively, the presence of K. pneumoniae, inparticular the presence of K. pneumoniae, in a sample, the methodcomprising contacting the sample with an antibody of aspects 8 or 9 ofthe invention and detecting the presence of antibody bound to materialin the sample.

In an 12^(th) aspect of the invention is provided a method fordetermining, quantitatively or qualitatively, the presence of antibodiesspecific for K. pneumoniae, in particular the presence of antibodiesspecific for K. pneumoniae, in a sample, the method comprisingcontacting the sample with a polypeptide of the invention and detectingthe presence of antibody that specifically bind said polypeptide.

In a 13^(th) aspect, the invention relates to a method for determining,quantitatively or qualitatively, the presence of a nucleic acidcharacteristic of K. pneumoniae, in particular the presence of a nucleicacid characteristic of K. pneumoniae, in a sample, the method comprisingcontacting the sample with a nucleic acid fragment of the invention anddetecting the presence of nucleic acid in the sample that hybridizes tosaid nucleic acid fragment.

In a 14^(th) aspect, the invention relates to a method for thepreparation of the polypeptide of the invention, comprising

-   -   culturing a transformed cell of the present invention, which is        capable of expressing the nucleic acid of the invention, under        conditions that facilitate that the transformed cell expresses        the nucleic acid fragment of the invention, which encodes a        polypeptide of the invention, and subsequently recovering said        polypeptide, or    -   preparing said polypeptide by means of solid or liquid phase        peptide synthesis.

In a 15^(th) aspect, the invention relates to a method for determiningwhether a substance, such as an antibody, is potentially useful fortreating infection with K. pneumoniae, the method comprising contactingthe polypeptide of the invention with the substance and subsequentlyestablishing whether the substance has at least one of the followingcharacteristics:

1) the ability to bind specifically to said polypeptide,

2) the ability to compeed with said polypeptide for specific binding toa ligand/receptor, and

3) the ability to specifically inactivate said polypeptide.

Finally, in a 16^(th) aspect, the invention relates to a method fordetermining whether a substance, such as a nucleic acid, is potentiallyuseful for treating infection with K. pneumoniae, the method comprisingcontacting the substance with the nucleic acid fragment of claim of theinvention and subsequently establishing whether the substance has eitherthe ability to

1) bind specifically to the nucleic acid fragment, or

2) bind specifically to a nucleic acid that hybridizes specifically withthe nucleic acid fragment.

LEGENDS TO THE FIGURE

FIGS. 1-6 show Kaplan-Meier survival plots in groups of mice subjectedto challenge infection with K. pneumoniae, i.e. survival plotcorresponding to the data in tables 1-6 herein.

FIGS. 1 and 3-6 show the survival plots from experiments 1 and 3-6,respectively, where mice received the infectious challenge via theintranasal route, whereas FIG. 2 shows the survival plots for micechallenged via the intraperitoneal route.

DETAILED DISCLOSURE OF THE INVENTION Definitions

The term “polypeptide” is in the present context intended to mean bothshort peptides of from 2 to 10 amino acid residues, oligopeptides offrom 11 to 100 amino acid residues, and polypeptides of more than 100amino acid residues. Furthermore, the term is also intended to includeproteins, i.e. functional biomolecules comprising at least onepolypeptide; when comprising at least two polypeptides, these may formcomplexes, be covalently linked, or may be non-covalently linked. Thepolypeptide (s) in a protein can be glycosylated and/or lipidated and/orcomprise prosthetic groups.

The term “subsequence” means any consecutive stretch of at least 3 aminoacids or, when relevant, of at least 3 nucleotides, derived directlyfrom a naturally occurring amino acid sequence or nucleic acid sequence,respectively

The term “amino acid sequence” s the order in which amino acid residues,connected by peptide bonds, lie in the chain in peptides and proteins.

The term “adjuvant” has its usual meaning in the art of vaccinetechnology, i.e. a substance or a composition of matter which is 1) notin itself capable of mounting a specific immune response against theimmunogen of the vaccine, but which is 2) nevertheless capable ofenhancing the immune response against the immunogen. Or, in other words,vaccination with the adjuvant alone does not provide an immune responseagainst the immunogen, vaccination with the immunogen may or may notgive rise to an immune response against the immunogen, but the combinedvaccination with immunogen and adjuvant induces an immune responseagainst the immunogen which is stronger than that induced by theimmunogen alone.

“Sequence identity” is in the context of the present inventiondetermined by comparing 2 optimally aligned sequences of equal length(e.g. DNA, RNA or amino acid) according to the following formula:(N_(ref)−N_(dif))·100/N_(ref), wherein N_(ref) is the number of residuesin one of the 2 sequences and N_(dif) is the number of residues whichare non-identical in the two sequences when they are aligned over theirentire lengths and in the same direction. So, two sequences5′-ATTCGGAACC-3′ and 5′-ATACGGGACC-3′ will provide the sequence identity80% (N_(ref)=10 and N_(dif)=2).

An “assembly of amino acids” means two or more amino acids boundtogether by physical or chemical means.

The “3D conformation” is the 3 dimensional structure of a biomoleculesuch as a protein. In monomeric polypeptides/proteins, the 3Dconformation is also termed “the tertiary structure” and denotes therelative locations in 3 dimensional space of the amino acid residuesforming the polypeptide.

“An immunogenic carrier” is a molecule or moiety to which an immunogenor a hapten can be coupled in order to enhance or enable the elicitationof an immune response against the immunogen/hapten. Immunogenic carriersare in classical cases relatively large molecules (such as tetanustoxoid, KLH, diphtheria toxoid etc.) which can be fused or conjugated toan immunogen/hapten, which is not sufficiently immunogenic in its ownright—typically, the immunogenic carrier is capable of eliciting astrong T-helper lymphocyte response against the combined substanceconstituted by the immunogen and the immunogenic carrier, and this inturn provides for improved responses against the immunogen byB-lymphocytes and cytotoxic lymphocytes. More recently, the largecarrier molecules have to a certain extent been substituted by so-calledpromiscuous T-helper epitopes, i.e. shorter peptides that are recognizedby a large fraction of HLA haplotypes in a population, and which elicitT-helper lymphocyte responses.

A “T-helper lymphocyte response” is an immune response elicited on thebasis of a peptide, which is able to bind to an MHC class II molecule(e.g. an HLA class II molecule) in an antigen-presenting cell and whichstimulates T-helper lymphocytes in an animal species as a consequence ofT-cell receptor recognition of the complex between the peptide and theMHC Class II molecule prese

An “immunogen” is a substance of matter which is capable of inducing anadaptive immune response in a host, whose immune system is confrontedwith the immunogen. As such, immunogens are a subset of the larger genus“antigens”, which are substances that can be recognized specifically bythe immune system (e.g. when bound by antibodies or, alternatively, whenfragments of the are antigens bound to MHC molecules are beingrecognized by T-cell receptors) but which are not necessarily capable ofinducing immunity—an antigen is, however, always capable of elicitingimmunity, meaning that a host that has an established memory immunityagainst the antigen will mount a specific immune response against theantigen.

A “hapten” is a small molecule, which can neither induce or elicit animmune response, but if conjugated to an immunogenic carrier, antibodiesor TCRs that recognize the hapten can be induced upon confrontation ofthe immune system with the hapten carrier conjugate.

An “adaptive immune response” is an immune response in response toconfrontation with an antigen or immunogen, where the immune response isspecific for antigene determinants of the antigen/immunogen—examples ofadaptive immune responses are induction of antigen specific antibodyproduction or antigen specific induction/activation of T helperlymphocytes or cytotoxic lymphocytes.

A “protective, adaptive immune response” is an antigen-specific immuneresponse induced in a subject as a reaction to immunization (artificialor natural) with an antigen, where the immune response is capable ofprotecting the subject against subsequent challenges with the antigen ora pathology-related agent that includes the antigen. Typically,prophylactic vaccination aims at establishing a protective adaptiveimmune response against one or several pathogens.

“Stimulation of the immune system” means that a substance or compositionof matter exhibits a general, non-specific immunostimulatory effect. Anumber of adjuvants and putative adjuvants (such as certain cytokines)share the ability to stimulate the immune system. The result of using animmunostimulating agent is an increased “alertness” of the immune systemmeaning that simultaneous or subsequent immunization with an immunogeninduces a significantly more effective immune response compared toisolated use of the immunogen.

Hybridization under “stringent conditions” is herein defined ashybridization performed under conditions by which a probe will hybridizeto its target sequence, to a detectably greater degree than to othersequences. Stringent conditions are target-sequence-dependent and willdiffer depending on the structure of the polynucleotide. By controllingthe stringency of the hybridization and/or washing conditions, targetsequences can be identified which are 100% complementary to a probe(homologous probing). Alternatively, stringency conditions can beadjusted to allow some mismatching in sequences so that lower degrees ofsimilarity are detected (heterologous probing). Specificity is typicallythe function of post-hybridization washes, the critical factors beingthe ionic strength and temperature of the final wash solution.Generally, stringent wash temperature conditions are selected to beabout 5° C. to about 2° C. lower than the melting point (Tm) for thespecific sequence at a defined ionic strength and pH. The melting point,or denaturation, of DNA occurs over a narrow temperature range andrepresents the disruption of the double helix into its complementarysingle strands. The process is described by the temperature of themidpoint of transition, Tm, which is also called the meltingtemperature. Formulas are available in the art for the determination ofmelting temperatures.

The term “animal” is in the present context in general intended todenote an animal species (preferably mammalian), such as Homo sapiens,Canis domesticus, etc. and not just one single animal. However, the termalso denotes a population of such an animal species, since it isimportant that the individuals immunized according to the method of theinvention substantially all will mount an immune response against theimmunogen of the present invention.

As used herein, the term “antibody” refers to a polypeptide or group ofpolypeptides composed of at least one antibody combining site. An“antibody combining site” is the three-dimensional binding space with aninternal surface shape and charge distribution complementary to thefeatures of an epitope of an antigen, which allows a binding of theantibody with the antigen. “Antibody” includes, for example, vertebrateantibodies, hybrid antibodies, chimeric antibodies, humanisedantibodies, altered antibodies, univalent antibodies, Fab proteins, andsingle domain antibodies.

“Specific binding” denotes binding between two substances which goesbeyond binding of either substance to randomly chosen substances andalso goes beyond simple association between substances that tend toaggregate because they share the same overall hydrophobicity orhydrophilicity. As such, specific binding usually involves a combinationof electrostatic and other interactions between two conformationallycomplementary areas on the two substances, meaning that the substancescan “recognize” each other in a complex mixture.

The term “vector” is used to refer to a carrier nucleic acid moleculeinto which a heterologous nucleic acid sequence can be inserted forintroduction into a cell where it can be replicated and expressed. Theterm further denotes certain biological vehicles useful for the samepurpose, e.g. viral vectors and phage—both these infectious agents arecapable of introducing a heterelogous nucleic acid sequence

The term “expression vector” refers to a vector containing a nucleicacid sequence coding for at least part of a gene product capable ofbeing transcribed. In some cases, when the transcription product is anmRNA molecule, this is in turn translated into a protein, polypeptide,or peptide.

SPECIFIC EMBODIMENTS OF THE INVENTION

The Polypeptides of the Invention

In some embodiments the at least or exactly 5 contiguous amino acidsreferred to in option b) in the definition of the first aspect of theinvention constitute at least or exactly 5, at least or exactly or atmost 6, at least or exactly or at most 7, at least or exactly or at most8, at least or exactly or at most 9, at least or exactly or at most 10,at least or exactly or at most 11, at least or exactly or at most 12, atleast or exactly or at most 13, at least or exactly or at most 14, atleast or exactly or at most 15, at least or exactly or at most 16, atleast or exactly or at most 17, at least or exactly or at most 18, atleast or exactly or at most 19, at least or exactly or at most 20, atleast or exactly or at most 21, at least or exactly or at most 22, atleast or exactly or at most 23, at least or exactly or at most 24, atleast or exactly or at most 25, at least or exactly or at most 26, atleast or exactly or at most 27 at least or exactly or at most 28, atleast or exactly or at most 29, at least or exactly or at most 30, atleast or exactly or at most 31, at least or exactly or at most 32, atleast or exactly or at most 33, at least or exactly or at most 34, atleast or exactly or at most 35, at least or exactly or at most 36, atleast or exactly or at most 37, at least or exactly or at most 38, atleast or exactly or at most 39, at least or exactly or at most 40, atleast or exactly or at most 41, at least or exactly or at most 42, atleast or exactly or at most 43, at least or exactly or at most 44, atleast or exactly or at most 45, at least or exactly or at most 46, atleast or exactly or at most 47, at least or exactly or at most 48, atleast or exactly or at most 49, at least or exactly or at most 50, atleast or exactly or at most 51, at least or exactly or at most 52, atleast or exactly or at most 53, at least or exactly or at most 54, atleast or exactly or at most 55, at least or exactly or at most 56, atleast or exactly or at most 57, at least or exactly or at most 58, atleast or exactly or at most 59, at least or exactly or at most 60, atleast or exactly or at most 61, at least or exactly or at most 62, atleast or exactly or at most 63, at least or exactly or at most 64, atleast or exactly or at most 65, at least or exactly or at most 66, atleast or exactly or at most 67, at least or exactly or at most 68, atleast or exactly or at most 69, at least or exactly or at most 70, atleast or exactly or at most 71, at least or exactly or at most 72, atleast or exactly or at most 73, at least or exactly or at most 74, atleast or exactly or at most 75, at least or exactly or at most 76, atleast or exactly or at most 77, at least or exactly or at most 78, atleast or exactly or at most 79, at least or exactly or at most 80, atleast or exactly or at most 81, at least or exactly or at most 82, atleast or exactly or at most 83, at least or exactly or at most 84, atleast or exactly or at most 85, at least or exactly or at most 86, atleast or exactly or at most 87, at least or exactly or at most 88, atleast or exactly or at most 89, at least or exactly or at most 90, atleast or exactly or at most 91, at least or exactly or at most 92, andat least or exactly or at most 93 contiguous amino acid residues.

The number of contiguous amino acids can be higher, for all of SEQ IDNOs: 2-30. Another way to phrase this is that for each of SEQ ID NOs:1-30, 93, and 94, the number of the contiguous amino acid residues is atleast or exactly or at most N−n, where N is the length of the sequenceID in question and n is any integer between N−5 and 0; that is, the atleast 5 contiguous amino acids can be at least any number between 5 andthe length of the reference sequence minus one, in increments of one.Consequently:

Insofar as embodiment b relates to SEQ ID NO: 2-30, 93, and 94, the atleast 5 contiguous amino acids referred to in option b) in thedefinition of the first aspect of the invention may also constitute atleast or exactly or at most 94, at least or exactly or at most 95, atleast or exactly or at most 96, at least or exactly or at most 97, atleast or exactly or at most 98, at least or exactly or at most 99, atleast or exactly or at most 100, at least or exactly or at most 101, atleast or exactly or at most 102, at least or exactly or at most 103, atleast or exactly or at most 104, at least or exactly or at most 105, atleast or exactly or at most 106, at least or exactly or at most 107, atleast or exactly or at most 108, at least or exactly or at most 109, atleast or exactly or at most 110, at least or exactly or at most 111, atleast or exactly or at most 112, at least or exactly or at most 113, atleast or exactly or at most 114, at least or exactly or at most 115, andat least or exactly or at most 116 contiguous amino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 3-30, 93, and 94, the atleast 5 contiguous amino acids referred to in option b) in thedefinition of the first aspect of the invention may also constitute atleast or exactly or at most 117, or at least or exactly or at most 118contiguous amino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 4-30, 93, and 94, the atleast 5 contiguous amino acids referred to in option b) in thedefinition of the first aspect of the invention may also constitute atleast or exactly or at most 119 contiguous amino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 5-30, 93, and 94, the atleast 5 contiguous amino acids referred to in option b) in thedefinition of the first aspect of the invention may also constitute atleast or exactly or at most 120 contiguous amino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 6-30, 93, and 94, the atleast 5 contiguous amino acids referred to in option b) in thedefinition of the first aspect of the invention may also constitute atleast or exactly or at most 121 contiguous amino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 7-30, 93, and 94, the atleast 5 contiguous amino acids referred to in option b) in thedefinition of the first aspect of the invention may also constitute atleast or exactly or at most 122, at least or exactly or at most 123, atleast or exactly or at most 124, at least or exactly or at most 125, atleast or exactly or at most 126, at least or exactly or at most 127, atleast or exactly or at most 128, at least or exactly or at most 129, atleast or exactly or at most 130, at least or exactly or at most 131, atleast or exactly or at most 132, at least or exactly or at most 133, atleast or exactly or at most 134, at least or exactly or at most 135, atleast or exactly or at most 136, at least or exactly or at most 137, atleast or exactly or at most 138, at least or exactly or at most 139, orat least or exactly or at most 140 contiguous amino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 8-30, 93, and 94, the atleast 5 contiguous amino acids referred to in option b) in thedefinition of the first aspect of the invention may also constitute atleast or exactly or at most 141, at least or exactly or at most 142, atleast or exactly or at most 143, at least or exactly or at most 144, atleast or exactly or at most 145, at least or exactly or at most 146, atleast or exactly or at most 147, at least or exactly or at most 148, atleast or exactly or at most 149, or at least or exactly or at most 150contiguous amino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 9-30, 93, and 94, the atleast 5 contiguous amino acids referred to in option b) in thedefinition of the first aspect of the invention may also constitute atleast or exactly or at most 151, at least or exactly or at most 152, atleast or exactly or at most 153, at least or exactly or at most 154, atleast or exactly or at most 155, at least or exactly or at most 156, atleast or exactly or at most 157, at least or exactly or at most 158, atleast or exactly or at most 159, at least or exactly or at most 160, atleast or exactly or at most 161, at least or exactly or at most 162, atleast or exactly or at most 163, at least or exactly or at most 164, atleast or exactly or at most 165, at least or exactly or at most 166, orat least or exactly or at most 167 contiguous amino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 10-30, 93, and 94, the atleast 5 contiguous amino acids referred to in option b) in thedefinition of the first aspect of the invention may also constitute atleast or exactly or at most 168, at least or exactly or at most 169, atleast or exactly or at most 170, at least or exactly or at most 171, atleast or exactly or at most 172, at least or exactly or at most 173, atleast or exactly or at most 174, at least or exactly or at most 175, atleast or exactly or at most 176, at least or exactly or at most 177, atleast or exactly or at most 178, at least or exactly or at most 179, atleast or exactly or at most 180, at least or exactly or at most 181, atleast or exactly or at most 182, at least or exactly or at most 183, atleast or exactly or at most 184, at least or exactly or at most 185, atleast or exactly or at most 186, at least or exactly or at most 187, atleast or exactly or at most 188, at least or exactly or at most 189, atleast or exactly or at most 190, at least or exactly or at most 191, orat least or exactly or at most 192 at least or exactly or at most 193,at least or exactly or at most 194, at least or exactly or at most 195,at least or exactly or at most 196, at least or exactly or at most 197,at least or exactly or at most 198, at least or exactly or at most 199,at least or exactly or at most 200, at least or exactly or at most 201,at least or exactly or at most 202, at least or exactly or at most 203,at least or exactly or at most 204, at least or exactly or at most 205,at least or exactly or at most 206, at least or exactly or at most 207,or at least or exactly or at most 208 at least or exactly or at most209, at least or exactly or at most 210, at least or exactly or at most211, at least or exactly or at most 212, at least or exactly or at most213, at least or exactly or at most 214, at least or exactly or at most215, at least or exactly or at most 216, at least or exactly or at most217, at least or exactly or at most 218, at least or exactly or at most219, at least or exactly or at most 220, at least or exactly or at most221, at least or exactly or at most 222, at least or exactly or at most223, at least or exactly or at most 224, at least or exactly or at most225, at least or exactly or at most 226, at least or exactly or at most227, or at least or exactly or at most 228 contiguous amino acidresidues.

Insofar as embodiment b relates to SEQ ID NO: 11-30, 93, and 94, the atleast 5 contiguous amino acids referred to in option b) in thedefinition of the first aspect of the invention may also constitute atleast or exactly or at most 229, at least or exactly or at most 230, atleast or exactly or at most 231, at least or exactly or at most 232, atleast or exactly or at most 233, at least or exactly or at most 234, atleast or exactly or at most 235, at least or exactly or at most 236, atleast or exactly or at most 237, at least or exactly or at most 238, atleast or exactly or at most 239, at least or exactly or at most 240, orat least or exactly or at most 241, at least or exactly or at most 242,at least or exactly or at most 243, at least or exactly or at most 244,or at least or exactly or at most 245 contiguous amino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 11-30 and 94, the at least5 contiguous amino acids referred to in option b) in the definition ofthe first aspect of the invention may also constitute at least orexactly or at most 246, at least or exactly or at most 247, at least orexactly or at most 248, at least or exactly or at most 249, at least orexactly or at most 250, at least or exactly or at most 251, at least orexactly or at most 252, at least or exactly or at most 253, at least orexactly or at most 254, at least or exactly or at most 255, at least orexactly or at most 256, at least or exactly or at most 257, at least orexactly or at most 258, at least or exactly or at most 259, at least orexactly or at most 260, at least or exactly or at most 261, at least orexactly or at most 262, at least or exactly or at most 263, at least orexactly or at most 264, at least or exactly or at most 265, at least orexactly or at most 266, at least or exactly or at most 267, at least orexactly or at most 268, at least or exactly or at most 269, at least orexactly or at most 270, at least or exactly or at most 271, at least orexactly or at most 272, at least or exactly or at most 273, at least orexactly or at most 274, at least or exactly or at most 275, at least orexactly or at most 276, at least or exactly or at most 277, at least orexactly or at most 278, at least or exactly or at most 279, at least orexactly or at most 280, at least or exactly or at most 281, at least orexactly or at most 282, at least or exactly or at most 283, at least orexactly or at most 284, at least or exactly or at most 285, at least orexactly or at most 286, at least or exactly or at most 287, at least orexactly or at most 288, at least or exactly or at most 289, at least orexactly or at most 290, at least or exactly or at most 291, at least orexactly or at most 292, at least or exactly or at most 293, at least orexactly or at most 294, at least or exactly or at most 295, at least orexactly or at most 296, at least or exactly or at most 297, at least orexactly or at most 298, at least or exactly or at most 299, at least orexactly or at most 300, at least or exactly or at most 301, at least orexactly or at most 302, at least or exactly or at most 303, at least orexactly or at most 304, at least or exactly or at most 305, at least orexactly or at most 306, at least or exactly or at most 307, at least orexactly or at most 308, at least or exactly or at most 309, at least orexactly or at most 310, at least or exactly or at most 311, at least orexactly or at most 312, at least or exactly or at most 313, at least orexactly or at most 314, at least or exactly or at most 315, at least orexactly or at most 316, at least or exactly or at most 317, at least orexactly or at most 318, at least or exactly or at most 319, at least orexactly or at most 320, or at least or exactly or at most 321 contiguousamino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 12-30 and 94, the at least5 contiguous amino acids referred to in option b) in the definition ofthe first aspect of the invention may also constitute at least orexactly or at most 322, at least or exactly or at most 323, at least orexactly or at most 324, at least or exactly or at most 325, or at leastor exactly or at most 326, at least or exactly or at most 327, at leastor exactly or at most 328, at least or exactly or at most 329, at leastor exactly or at most 330, at least or exactly or at most 331, at leastor exactly or at most 332, at least or exactly or at most 333, at leastor exactly or at most 334, at least or exactly or at most 335, at leastor exactly or at most 336, at least or exactly or at most 337, at leastor exactly or at most 338, at least or exactly or at most 339, at leastor exactly or at most 340, at least or exactly or at most 341, at leastor exactly or at most 342, at least or exactly or at most 343, at leastor exactly or at most 344, at least or exactly or at most 345, at leastor exactly or at most 346, at least or exactly or at most 347, at leastor exactly or at most 348, at least or exactly or at most 349, at leastor exactly or at most 350, at least or exactly or at most 351, at leastor exactly or at most 352, at least or exactly or at most 353, at leastor exactly or at most 354, at least or exactly or at most 355, at leastor exactly or at most 356 at least or exactly or at most 357, at leastor exactly or at most 358, at least or exactly or at most 359, at leastor exactly or at most 360, at least or exactly or at most 361, at leastor exactly or at most 362, at least or exactly or at most 363, at leastor exactly or at most 364, at least or exactly or at most 365, at leastor exactly or at most 366, at least or exactly or at most 367, at leastor exactly or at most 368, at least or exactly or at most 369, at leastor exactly or at most 370, at least or exactly or at most 371, at leastor exactly or at most 372, at least or exactly or at most 373, at leastor exactly or at most 374, or at least or exactly or at most 375contiguous amino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 13-30 and 94, the at least5 contiguous amino acids referred to in option b) in the definition ofthe first aspect of the invention may also constitute at least orexactly or at most 376, at least or exactly or at most 377, at least orexactly or at most 378, at least or exactly or at most 379, at least orexactly or at most 380, or at least or exactly or at most 381 contiguousamino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 14-30 and 94, the at least5 contiguous amino acids referred to in option b) in the definition ofthe first aspect of the invention may also constitute at least orexactly or at most 382, at least or exactly or at most 383, at least orexactly or at most 384, at least or exactly or at most 385, at least orexactly or at most 386, at least or exactly or at most 387, at least orexactly or at most 388, at least or exactly or at most 389, at least orexactly or at most 390, at least or exactly or at most 391, at least orexactly or at most 392, at least or exactly or at most 393, at least orexactly or at most 394, at least or exactly or at most 395, at least orexactly or at most 396, at least or exactly or at most 397, at least orexactly or at most 398, at least or exactly or at most 399, at least orexactly or at most 400, at least or exactly or at most 401, at least orexactly or at most 402, at least or exactly or at most 403, at least orexactly or at most 404, at least or exactly or at most 405, at least orexactly or at most 406, at least or exactly or at most 407, at least orexactly or at most 408, at least or exactly or at most 409, at least orexactly or at most 410, at least or exactly or at most 411, at least orexactly or at most 412, at least or exactly or at most 413, at least orexactly or at most 414, at least or exactly or at most 415, at least orexactly or at most 416, at least or exactly or at most 417, at least orexactly or at most 418, at least or exactly or at most 419, at least orexactly or at most 420, at least or exactly or at most 421, at least orexactly or at most 422, at least or exactly or at most 423, at least orexactly or at most 424, at least or exactly or at most 425, at least orexactly or at most 426, or at least or exactly or at most 427 contiguousamino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 15-30 and 94, the at least5 contiguous amino acids referred to in option b) in the definition ofthe first aspect of the invention may also constitute at least orexactly or at most 428, at least or exactly or at most 429, at least orexactly or at most 430, at least or exactly or at most 431, at least orexactly or at most 432, at least or exactly or at most 433, at least orexactly or at most 434, at least or exactly or at most 435, at least orexactly or at most 436, at least or exactly or at most 437, at least orexactly or at most 438, at least or exactly or at most 439, or at leastor exactly or at most 440 contiguous amino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 16-30 and 94, the at least5 contiguous amino acids referred to in option b) in the definition ofthe first aspect of the invention may also constitute at least orexactly or at most 441, at least or exactly or at most 442, at least orexactly or at most 443, at least or exactly or at most 444, at least orexactly or at most 445, at least or exactly or at most 446, at least orexactly or at most 447, at least or exactly or at most 448, at least orexactly or at most 449, at least or exactly or at most 450, at least orexactly or at most 451, at least or exactly or at most 452, at least orexactly or at most 453, at least or exactly or at most 454, at least orexactly or at most 455, at least or exactly or at most 456, at least orexactly or at most 457, at least or exactly or at most 458, at least orexactly or at most 459, at least or exactly or at most 460, at least orexactly or at most 461, at least or exactly or at most 462, at least orexactly or at most 463, at least or exactly or at most 464, at least orexactly or at most 465, at least or exactly or at most 466, at least orexactly or at most 467, at least or exactly or at most 468, at least orexactly or at most 469, at least or exactly or at most 470, at least orexactly or at most 471, at least or exactly or at most 472, at least orexactly or at most 473, at least or exactly or at most 474, at least orexactly or at most 475, at least or exactly or at most 476, at least orexactly or at most 477, at least or exactly or at most 478, at least orexactly or at most 479, at least or exactly or at most 480, at least orexactly or at most 481, at least or exactly or at most 482, or at leastor exactly or at most 483 contiguous amino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 17-30 and 94, the at least5 contiguous amino acids referred to in option b) in the definition ofthe first aspect of the invention may also constitute at least orexactly or at most 484, at least or exactly or at most 485, at least orexactly or at most 486, at least or exactly or at most 487, at least orexactly or at most 488, at least or exactly or at most 489, at least orexactly or at most 490, at least or exactly or at most 491, at least orexactly or at most 492, at least or exactly or at most 493, or at leastor exactly or at most 494 at least or exactly or at most 495, at leastor exactly or at most 496, at least or exactly or at most 497, at leastor exactly or at most 498, at least or exactly or at most 499, at leastor exactly or at most 500, at least or exactly or at most 501, at leastor exactly or at most 502, at least or exactly or at most 503, at leastor exactly or at most 504, at least or exactly or at most 505, at leastor exactly or at most 506, at least or exactly or at most 507, at leastor exactly or at most 508 at least or exactly or at most 509, at leastor exactly or at most 510, at least or exactly or at most 511, at leastor exactly or at most 512, at least or exactly or at most 513, at leastor exactly or at most 514, at least or exactly or at most 515, at leastor exactly or at most 516, at least or exactly or at most 517, at leastor exactly or at most 518, at least or exactly or at most 519, at leastor exactly or at most 520, at least or exactly or at most 521, at leastor exactly or at most 522, at least or exactly or at most 523, at leastor exactly or at most 524, at least or exactly or at most 525, at leastor exactly or at most 526, at least or exactly or at most 527, at leastor exactly or at most 528, at least or exactly or at most 529, at leastor exactly or at most 530, at least or exactly or at most 531, at leastor exactly or at most 532, at least or exactly or at most 533, or atleast or exactly or at most 534 contiguous amino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 18-30 and 94, the at least5 contiguous amino acids referred to in option b) in the definition ofthe first aspect of the invention may also constitute at least orexactly or at most 535, at least or exactly or at most 536, at least orexactly or at most 537, at least or exactly or at most 538, at least orexactly or at most 539, at least or exactly or at most 540, at least orexactly or at most 541, at least or exactly or at most 542, at least orexactly or at most 543, at least or exactly or at most 544, at least orexactly or at most 545, at least or exactly or at most 546, at least orexactly or at most 547, at least or exactly or at most 548, at least orexactly or at most 549, at least or exactly or at most 550, at least orexactly or at most 551, at least or exactly or at most 552, at least orexactly or at most 553, at least or exactly or at most 554, at least orexactly or at most 555, at least or exactly or at most 556, at least orexactly or at most 557, at least or exactly or at most 558, at least orexactly or at most 559, at least or exactly or at most 560, at least orexactly or at most 561, at least or exactly or at most 562, or at leastor exactly or at most 563, 427 at least or exactly or at most 564, atleast or exactly or at most 565, at least or exactly or at most 566, atleast or exactly or at most 567, at least or exactly or at most 568, atleast or exactly or at most 569, at least or exactly or at most 570, atleast or exactly or at most 571, at least or exactly or at most 572, atleast or exactly or at most 573, at least or exactly or at most 574, atleast or exactly or at most 575, at least or exactly or at most 576, atleast or exactly or at most 577, at least or exactly or at most 578, atleast or exactly or at most 579, at least or exactly or at most 580, atleast or exactly or at most 581, at least or exactly or at most 582, atleast or exactly or at most 583, at least or exactly or at most 584, atleast or exactly or at most 585, at least or exactly or at most 586, atleast or exactly or at most 587, at least or exactly or at most 588, atleast or exactly or at most 589, at least or exactly or at most 590, atleast or exactly or at most 591, at least or exactly or at most 592, atleast or exactly or at most 593, at least or exactly or at most 594, atleast or exactly or at most 595, or at least or exactly or at most 596contiguous amino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 19-30 and 94, the at least5 contiguous amino acids referred to in option b) in the definition ofthe first aspect of the invention may also constitute at least orexactly or at most 597, at least or exactly or at most 598, at least orexactly or at most 599, at least or exactly or at most 600, at least orexactly or at most 601, at least or exactly or at most 602, at least orexactly or at most 603, at least or exactly or at most 604, at least orexactly or at most 605, at least or exactly or at most 606, at least orexactly or at most 607, at least or exactly or at most 608, at least orexactly or at most 609, at least or exactly or at most 610, at least orexactly or at most 611, at least or exactly or at most 612, at least orexactly or at most 613, at least or exactly or at most 614, at least orexactly or at most 615, at least or exactly or at most 616, at least orexactly or at most 617, at least or exactly or at most 618, at least orexactly or at most 619, at least or exactly or at most 620, at least orexactly or at most 621, at least or exactly or at most 622, or at leastor exactly or at most 623 contiguous amino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 20-30 and 94, the at least5 contiguous amino acids referred to in option b) in the definition ofthe first aspect of the invention may also constitute at least orexactly or at most 624, at least or exactly or at most 625, at least orexactly or at most 626, at least or exactly or at most 627, at least orexactly or at most 628, at least or exactly or at most 629, at least orexactly or at most 630, at least or exactly or at most 631, at least orexactly or at most 632, at least or exactly or at most 633, at least orexactly or at most 634, at least or exactly or at most 635, at least orexactly or at most 636, at least or exactly or at most 637, at least orexactly or at most 638, at least or exactly or at most 639, at least orexactly or at most 640, at least or exactly or at most 641, at least orexactly or at most 642, at least or exactly or at most 643, at least orexactly or at most 644, at least or exactly or at most 645, at least orexactly or at most 646, at least or exactly or at most 647, at least orexactly or at most 648, at least or exactly or at most 649, at least orexactly or at most 650, at least or exactly or at most 651, at least orexactly or at most 652, at least or exactly or at most 653, at least orexactly or at most 654, at least or exactly or at most 655, or at leastor exactly or at most 656 contiguous amino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 21-30 and 94, the at least5 contiguous amino acids referred to in option b) in the definition ofthe first aspect of the invention may also constitute at least orexactly or at most 657, at least or exactly or at most 658, at least orexactly or at most 659, at least or exactly or at most 660, at least orexactly or at most 661, at least or exactly or at most 662, at least orexactly or at most 663, at least or exactly or at most 664, at least orexactly or at most 665, at least or exactly or at most 666, at least orexactly or at most 667, at least or exactly or at most 668, at least orexactly or at most 669, at least or exactly or at most 670, at least orexactly or at most 671, at least or exactly or at most 672, at least orexactly or at most 673, or at least or exactly or at most 674 contiguousamino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 22-30 and 94, the at least5 contiguous amino acids referred to in option b) in the definition ofthe first aspect of the invention may also constitute at least orexactly or at most 675, at least or exactly or at most 676, at least orexactly or at most 677, at least or exactly or at most 678, at least orexactly or at most 679, at least or exactly or at most 680, at least orexactly or at most 681, at least or exactly or at most 682, at least orexactly or at most 683, at least or exactly or at most 684, at least orexactly or at most 685, at least or exactly or at most 686, at least orexactly or at most 687, at least or exactly or at most 688, at least orexactly or at most 689, at least or exactly or at most 690, at least orexactly or at most 691, at least or exactly or at most 692, at least orexactly or at most 693, at least or exactly or at most 694, at least orexactly or at most 695, at least or exactly or at most 696, at least orexactly or at most 697, at least or exactly or at most 698, at least orexactly or at most 699, or at least or exactly or at most 700 contiguousamino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 23-30 and 94, the at least5 contiguous amino acids referred to in option b) in the definition ofthe first aspect of the invention may also constitute at least orexactly or at most 701, at least or exactly or at most 702, at least orexactly or at most 703, at least or exactly or at most 704, at least orexactly or at most 705, at least or exactly or at most 706, at least orexactly or at most 707, at least or exactly or at most 708, at least orexactly or at most 709, at least or exactly or at most 710, at least orexactly or at most 711, at least or exactly or at most 712, at least orexactly or at most 713, at least or exactly or at most 714, at least orexactly or at most 715, at least or exactly or at most 716, at least orexactly or at most 717, at least or exactly or at most 718, at least orexactly or at most 719, at least or exactly or at most 720, at least orexactly or at most 721, at least or exactly or at most 722, at least orexactly or at most 723, at least or exactly or at most 724, at least orexactly or at most 725, at least or exactly or at most 726, at least orexactly or at most 727, at least or exactly or at most 728, at least orexactly or at most 729, at least or exactly or at most 730, at least orexactly or at most 731, at least or exactly or at most 732, at least orexactly or at most 733, at least or exactly or at most 734, at least orexactly or at most 735, at least or exactly or at most 736, at least orexactly or at most 737, at least or exactly or at most 738, at least orexactly or at most 739, at least or exactly or at most 740, at least orexactly or at most 741, at least or exactly or at most 742, at least orexactly or at most 743, at least or exactly or at most 744, at least orexactly or at most 745, at least or exactly or at most 746, at least orexactly or at most 747, at least or exactly or at most 748, at least orexactly or at most 749, at least or exactly or at most 750, or at leastor exactly or at most 751 contiguous amino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 24-30 and 94, the at least5 contiguous amino acids referred to in option b) in the definition ofthe first aspect of the invention may also constitute at least orexactly or at most 752, at least or exactly or at most 753, at least orexactly or at most 754, at least or exactly or at most 755, at least orexactly or at most 756, at least or exactly or at most 757, at least orexactly or at most 758, at least or exactly or at most 759, or at leastor exactly or at most 760 contiguous amino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 25-30 and 94, the at least5 contiguous amino acids referred to in option b) in the definition ofthe first aspect of the invention may also constitute at least orexactly or at most 761, at least or exactly or at most 762, at least orexactly or at most 763, at least or exactly or at most 764, at least orexactly or at most 765, at least or exactly or at most 766, at least orexactly or at most 767, at least or exactly or at most 768, at least orexactly or at most 769, at least or exactly or at most 770, at least orexactly or at most 771, at least or exactly or at most 772, at least orexactly or at most 773, at least or exactly or at most 774, at least orexactly or at most 775, at least or exactly or at most 776, at least orexactly or at most 777, at least or exactly or at most 778, at least orexactly or at most 779, at least or exactly or at most 780, at least orexactly or at most 781, at least or exactly or at most 782, at least orexactly or at most 783, at least or exactly or at most 784, at least orexactly or at most 785, at least or exactly or at most 786, at least orexactly or at most 787, at least or exactly or at most 788, or at leastor exactly or at most 789 contiguous amino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 26-30 and 94, the at least5 contiguous amino acids referred to in option b) in the definition ofthe first aspect of the invention may also constitute at least orexactly or at most 790, at least or exactly or at most 791, at least orexactly or at most 792, at least or exactly or at most 793, at least orexactly or at most 794, at least or exactly or at most 795, at least orexactly or at most 796, at least or exactly or at most 797, at least orexactly or at most 798, at least or exactly or at most 799, at least orexactly or at most 800, at least or exactly or at most 801, at least orexactly or at most 802, at least or exactly or at most 803, at least orexactly or at most 804, at least or exactly or at most 805, at least orexactly or at most 806, at least or exactly or at most 807, or at leastor exactly or at most 808 contiguous amino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 27-30 and 94, the at least5 contiguous amino acids referred to in option b) in the definition ofthe first aspect of the invention may also constitute at least orexactly or at most 809, at least or exactly or at most 810, at least orexactly or at most 811, at least or exactly or at most 812, at least orexactly or at most 813, at least or exactly or at most 815, at least orexactly or at most 816, at least or exactly or at most 817, at least orexactly or at most 818, at least or exactly or at most 819, at least orexactly or at most 820, at least or exactly or at most 821, at least orexactly or at most 811, at least or exactly or at most 823, at least orexactly or at most 824, at least or exactly or at most 825, at least orexactly or at most 826, at least or exactly or at most 827, at least orexactly or at most 828, at least or exactly or at most 829, at least orexactly or at most 830, at least or exactly or at most 831, at least orexactly or at most 832, at least or exactly or at most 833, at least orexactly or at most 834, at least or exactly or at most 835, at least orexactly or at most 836, at least or exactly or at most 837, at least orexactly or at most 838, at least or exactly or at most 839, at least orexactly or at most 840, at least or exactly or at most 841, at least orexactly or at most 842, at least or exactly or at most 843, at least orexactly or at most 844, at least or exactly or at most 845, at least orexactly or at most 846, at least or exactly or at most 847, at least orexactly or at most 848, at least or exactly or at most 849, at least orexactly or at most 850, at least or exactly or at most 851, at least orexactly or at most 852, at least or exactly or at most 853, at least orexactly or at most 854, at least or exactly or at most 855, at least orexactly or at most 856, at least or exactly or at most 857, at least orexactly or at most 858, at least or exactly or at most 859, at least orexactly or at most 860, at least or exactly or at most 861, at least orexactly or at most 862, at least or exactly or at most 863, at least orexactly or at most 864, at least or exactly or at most 865, at least orexactly or at most 866, at least or exactly or at most 867, at least orexactly or at most 868, at least or exactly or at most 869, at least orexactly or at most 870, at least or exactly or at most 871, at least orexactly or at most 872, at least or exactly or at most 873, at least orexactly or at most 874, at least or exactly or at most 875, at least orexactly or at most 876, at least or exactly or at most 877, at least orexactly or at most 878, at least or exactly or at most 879, at least orexactly or at most 880, at least or exactly or at most 881, at least orexactly or at most 882, at least or exactly or at most 883, at least orexactly or at most 884, at least or exactly or at most 885, at least orexactly or at most 886, at least or exactly or at most 887, at least orexactly or at most 888, at least or exactly or at most 889, at least orexactly or at most 890, at least or exactly or at most 891, at least orexactly or at most 892, at least or exactly or at most 893, at least orexactly or at most 894, or at least or exactly or at most 895 contiguousamino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 28-30 and 94, the at least5 contiguous amino acids referred to in option b) in the definition ofthe first aspect of the invention may also constitute at least orexactly or at most 896, at least or exactly or at most 897, at least orexactly or at most 898, at least or exactly or at most 899, at least orexactly or at most 900, at least or exactly or at most 901, at least orexactly or at most 902, at least or exactly or at most 903, at least orexactly or at most 904, at least or exactly or at most 905, at least orexactly or at most 906, at least or exactly or at most 907, at least orexactly or at most 908, at least or exactly or at most 909, at least orexactly or at most 910, at least or exactly or at most 911, at least orexactly or at most 912, at least or exactly or at most 913, at least orexactly or at most 914, at least or exactly or at most 915, at least orexactly or at most 916, at least or exactly or at most 917, at least orexactly or at most 918, at least or exactly or at most 919, at least orexactly or at most 920, at least or exactly or at most 921, at least orexactly or at most 922, at least or exactly or at most 923, at least orexactly or at most 924, at least or exactly or at most 925, at least orexactly or at most 926, at least or exactly or at most 927, at least orexactly or at most 928, at least or exactly or at most 929, at least orexactly or at most 930, at least or exactly or at most 931, at least orexactly or at most 932, at least or exactly or at most 933, at least orexactly or at most 934, at least or exactly or at most 935, at least orexactly or at most 936, at least or exactly or at most 937, at least orexactly or at most 938, at least or exactly or at most 939, at least orexactly or at most 940, at least or exactly or at most 941, at least orexactly or at most 942, at least or exactly or at most 943, at least orexactly or at most 944, at least or exactly or at most 945, at least orexactly or at most 946, at least or exactly or at most 947, at least orexactly or at most 948, at least or exactly or at most 949, at least orexactly or at most 950, at least or exactly or at most 951, at least orexactly or at most 952, at least or exactly or at most 953, at least orexactly or at most 954, at least or exactly or at most 955, at least orexactly or at most 956, at least or exactly or at most 957, at least orexactly or at most 958, at least or exactly or at most 959, at least orexactly or at most 960, at least or exactly or at most 961, at least orexactly or at most 962, at least or exactly or at most 963, at least orexactly or at most 964, at least or exactly or at most 965, at least orexactly or at most 966, at least or exactly or at most 967, at least orexactly or at most 968, at least or exactly or at most 969, at least orexactly or at most 970, at least or exactly or at most 971, at least orexactly or at most 972, at least or exactly or at most 973, at least orexactly or at most 974, at least or exactly or at most 975, at least orexactly or at most 976, at least or exactly or at most 977, at least orexactly or at most 978, at least or exactly or at most 979, at least orexactly or at most 980, at least or exactly or at most 981, at least orexactly or at most 982, at least or exactly or at most 983, at least orexactly or at most 984, at least or exactly or at most 985, at least orexactly or at most 986, at least or exactly or at most 987, at least orexactly or at most 988, at least or exactly or at most 989, at least orexactly or at most 990, at least or exactly or at most 991, at least orexactly or at most 992, at least or exactly or at most 993, at least orexactly or at most 994, at least or exactly or at most 995, at least orexactly or at most 996, at least or exactly or at most 997, at least orexactly or at most 998, at least or exactly or at most 999, at least orexactly or at most 1000, at least or exactly or at most 1001, at leastor exactly or at most 1002, at least or exactly or at most 1003, atleast or exactly or at most 1004, at least or exactly or at most 1005,at least or exactly or at most 1006, at least or exactly or at most1007, at least or exactly or at most 1008, at least or exactly or atmost 1009, at least or exactly or at most 1010, at least or exactly orat most 1011, at least or exactly or at most 1012, at least or exactlyor at most 1013, at least or exactly or at most 1014, at least orexactly or at most 1015, at least or exactly or at most 1016, at leastor exactly or at most 1017, at least or exactly or at most 1018, atleast or exactly or at most 1019, at least or exactly or at most 1020,at least or exactly or at most 1021, at least or exactly or at most1022, at least or exactly or at most 1023, at least or exactly or atmost 1024, at least or exactly or at most 1025, at least or exactly orat most 1026, at least or exactly or at most 1027, at least or exactlyor at most 1028, at least or exactly or at most 1029, at least orexactly or at most 1030, at least or exactly or at most 1031, at leastor exactly or at most 1032, at least or exactly or at most 1033, atleast or exactly or at most 1034, at least or exactly or at most 1035,at least or exactly or at most 1036, at least or exactly or at most1037, at least or exactly or at most 1038, at least or exactly or atmost 1039, at least or exactly or at most 1040, at least or exactly orat most 1041, at least or exactly or at most 1042, at least or exactlyor at most 1043, at least or exactly or at most 1044, at least orexactly or at most 1045, at least or exactly or at most 1046, at leastor exactly or at most 1047, at least or exactly or at most 1048, atleast or exactly or at most 1049, at least or exactly or at most 1050,at least or exactly or at most 1051, at least or exactly or at most1052, at least or exactly or at most 1053, at least or exactly or atmost 1054, at least or exactly or at most 1055, at least or exactly orat most 1056, at least or exactly or at most 1057, at least or exactlyor at most 1058, at least or exactly or at most 1059, at least orexactly or at most 1060, at least or exactly or at most 1061, at leastor exactly or at most 1062, at least or exactly or at most 1063, atleast or exactly or at most 1064, at least or exactly or at most 1065,at least or exactly or at most 1066, at least or exactly or at most1067, at least or exactly or at most 1068, at least or exactly or atmost 1069, at least or exactly or at most 1070, at least or exactly orat most 1071, at least or exactly or at most 1072, at least or exactlyor at most 1073, at least or exactly or at most 1074, at least orexactly or at most 1075, or at least or exactly or at most 1076contiguous amino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 29-30 and 94, the at least5 contiguous amino acids referred to in option b) in the definition ofthe first aspect of the invention may also constitute at least orexactly or at most 1077, at least or exactly or at most 1078, at leastor exactly or at most 1079, at least or exactly or at most 1080, atleast or exactly or at most 1081, at least or exactly or at most 1082,at least or exactly or at most 1083, at least or exactly or at most1084, at least or exactly or at most 1085, at least or exactly or atmost 1086, at least or exactly or at most 1087, at least or exactly orat most 1088, at least or exactly or at most 1089, at least or exactlyor at most 1090, at least or exactly or at most 1091, at least orexactly or at most 1092, at least or exactly or at most 1093, at leastor exactly or at most 1094, at least or exactly or at most 1095, atleast or exactly or at most 1096, at least or exactly or at most 1097,at least or exactly or at most 1098, at least or exactly or at most1099, at least or exactly or at most 1100, at least or exactly or atmost 1101, at least or exactly or at most 1102, at least or exactly orat most 1103, at least or exactly or at most 1104, at least or exactlyor at most 1105, at least or exactly or at most 1106, at least orexactly or at most 1107, at least or exactly or at most 1108, at leastor exactly or at most 1109, at least or exactly or at most 1110, atleast or exactly or at most 1111, at least or exactly or at most 1112,at least or exactly or at most 1113, at least or exactly or at most1114, at least or exactly or at most 1115, at least or exactly or atmost 1116, at least or exactly or at most 1117, at least or exactly orat most 1118, at least or exactly or at most 1119, at least or exactlyor at most 1120, at least or exactly or at most 1121, at least orexactly or at most 1122, at least or exactly or at most 1123, at leastor exactly or at most 1124, at least or exactly or at most 1125, atleast or exactly or at most 1126, at least or exactly or at most 1127,at least or exactly or at most 1128, at least or exactly or at most1129, at least or exactly or at most 1130, at least or exactly or atmost 1131, at least or exactly or at most 1132, at least or exactly orat most 1133, at least or exactly or at most 1134, at least or exactlyor at most 1135, at least or exactly or at most 1136, at least orexactly or at most 1137, at least or exactly or at most 1138, at leastor exactly or at most 1139, at least or exactly or at most 1140, atleast or exactly or at most 1141, at least or exactly or at most 1142,at least or exactly or at most 1143, at least or exactly or at most1144, at least or exactly or at most 1145, at least or exactly or atmost 1146, at least or exactly or at most 1147, at least or exactly orat most 1148, at least or exactly or at most 1149, at least or exactlyor at most 1150, at least or exactly or at most 1151, at least orexactly or at most 1152, at least or exactly or at most 1153, at leastor exactly or at most 1154, at least or exactly or at most 1155, atleast or exactly or at most 1156, at least or exactly or at most 1157,or at least or exactly or at most 1158 contiguous amino acid residues.

Insofar as embodiment b relates to SEQ ID NO: 30 and 94, the at least 5contiguous amino acids referred to in option b) in the definition of thefirst aspect of the invention may also constitute at least or exactly orat most 1159, at least or exactly or at most 1160, at least or exactlyor at most 1161, at least or exactly or at most 1162, at least orexactly or at most 1163, at least or exactly or at most 1164, at leastor exactly or at most 1165, at least or exactly or at most 1166, atleast or exactly or at most 1167, at least or exactly or at most 1168,at least or exactly or at most 1169, at least or exactly or at most1170, at least or exactly or at most 1171, at least or exactly or atmost 1172, at least or exactly or at most 1173, at least or exactly orat most 1174, at least or exactly or at most 1175, at least or exactlyor at most 1176, at least or exactly or at most 1177, at least orexactly or at most 1178, at least or exactly or at most 1179, at leastor exactly or at most 1180, at least or exactly or at most 1181, atleast or exactly or at most 1182, at least or exactly or at most 1183,at least or exactly or at most 1184, at least or exactly or at most1185, at least or exactly or at most 1186, at least or exactly or atmost 1187, at least or exactly or at most 1188, at least or exactly orat most 1189, at least or exactly or at most 1190, at least or exactlyor at most 1191, at least or exactly or at most 1192, at least orexactly or at most 1193, at least or exactly or at most 1194, at leastor exactly or at most 1195, at least or exactly or at most 1196, atleast or exactly or at most 1197, at least or exactly or at most 1198,at least or exactly or at most 1199, at least or exactly or at most1200, at least or exactly or at most 1201, at least or exactly or atmost 1202, at least or exactly or at most 1203, at least or exactly orat most 1204, at least or exactly or at most 1205, at least or exactlyor at most 1206, at least or exactly or at most 1207, at least orexactly or at most 1208, at least or exactly or at most 1209, at leastor exactly or at most 1210, at least or exactly or at most 1211, atleast or exactly or at most 1212, at least or exactly or at most 1213,at least or exactly or at most 1214, at least or exactly or at most1215, at least or exactly or at most 1216, at least or exactly or atmost 1217, at least or exactly or at most 1218, at least or exactly orat most 1219, at least or exactly or at most 1220, at least or exactlyor at most 1221, at least or exactly or at most 1222, at least orexactly or at most 1223, at least or exactly or at most 1224, at leastor exactly or at most 1225, at least or exactly or at most 1226, atleast or exactly or at most 1227, at least or exactly or at most 1228,at least or exactly or at most 1229, at least or exactly or at most1230, at least or exactly or at most 1231, at least or exactly or atmost 1232, at least or exactly or at most 1233, at least or exactly orat most 1234, at least or exactly or at most 1235, at least or exactlyor at most 1236, at least or exactly or at most 1237, at least orexactly or at most 1238, at least or exactly or at most 1239, at leastor exactly or at most 1240, at least or exactly or at most 1241, atleast or exactly or at most 1242, at least or exactly or at most 1243,at least or exactly or at most 1244, at least or exactly or at most1245, at least or exactly or at most 1246, at least or exactly or atmost 1247, at least or exactly or at most 1248, at least or exactly orat most 1249, at least or exactly or at most 1250, at least or exactlyor at most 1251, at least or exactly or at most 1252, at least orexactly or at most 1253, at least or exactly or at most 1254, at leastor exactly or at most 1255, at least or exactly or at most 1256, atleast or exactly or at most 1257, at least or exactly or at most 1258,at least or exactly or at most 1259, at least or exactly or at most1260, at least or exactly or at most 1261, at least or exactly or atmost 1262, at least or exactly or at most 1263, at least or exactly orat most 1264, at least or exactly or at most 1265, at least or exactlyor at most 1266, at least or exactly or at most 1267, at least orexactly or at most 1268, at least or exactly or at most 1269, at leastor exactly or at most 1270, at least or exactly or at most 1271, atleast or exactly or at most 1272, at least or exactly or at most 1273,at least or exactly or at most 1274, at least or exactly or at most1275, at least or exactly or at most 1276, at least or exactly or atmost 1277, at least or exactly or at most 1278, at least or exactly orat most 1279, at least or exactly or at most 1280, at least or exactlyor at most 1281, at least or exactly or at most 1282, at least orexactly or at most 1283, at least or exactly or at most 1284, at leastor exactly or at most 1285, at least or exactly or at most 1286, atleast or exactly or at most 1287, at least or exactly or at most 1288,at least or exactly or at most 1289, at least or exactly or at most1290, at least or exactly or at most 1291, at least or exactly or atmost 1292, at least or exactly or at most 1293, at least or exactly orat most 1294, at least or exactly or at most 1295, at least or exactlyor at most 1296, at least or exactly or at most 1297, at least orexactly or at most 1298, at least or exactly or at most 1299, at leastor exactly or at most 1300, at least or exactly or at most 1301, atleast or exactly or at most 1302, at least or exactly or at most 1303,at least or exactly or at most 1304, at least or exactly or at most1305, at least or exactly or at most 1306, at least or exactly or atmost 1307, at least or exactly or at most 1308, at least or exactly orat most 1309, at least or exactly or at most 1310, at least or exactlyor at most 1311, at least or exactly or at most 1312, at least orexactly or at most 1313, at least or exactly or at most 1314, at leastor exactly or at most 1315, at least or exactly or at most 1316, atleast or exactly or at most 1317, at least or exactly or at most 1318,at least or exactly or at most 1319, at least or exactly or at most1320, at least or exactly or at most 1321, at least or exactly or atmost 1322, at least or exactly or at most 1323, at least or exactly orat most 1324, at least or exactly or at most 1325, at least or exactlyor at most 1326, at least or exactly or at most 1327, at least orexactly or at most 1328, at least or exactly or at most 1329, at leastor exactly or at most 1330, at least or exactly or at most 1331, atleast or exactly or at most 1332, at least or exactly or at most 1333,at least or exactly or at most 1334, at least or exactly or at most1335, at least or exactly or at most 1336, at least or exactly or atmost 1337, at least or exactly or at most 1338, at least or exactly orat most 1339, at least or exactly or at most 1340, at least or exactlyor at most 1341, at least or exactly or at most 1342, at least orexactly or at most 1343, at least or exactly or at most 1344, at leastor exactly or at most 1345, at least or exactly or at most 1346, atleast or exactly or at most 1347, at least or exactly or at most 1348,at least or exactly or at most 1349, at least or exactly or at most1350, at least or exactly or at most 1351, at least or exactly or atmost 1352, at least or exactly or at most 1353, at least or exactly orat most 1354, at least or exactly or at most 1355, at least or exactlyor at most 1356, at least or exactly or at most 1357, at least orexactly or at most 1358, at least or exactly or at most 1359, at leastor exactly or at most 1360, at least or exactly or at most 1361, atleast or exactly or at most 1362, at least or exactly or at most 1363,at least or exactly or at most 1364, at least or exactly or at most1365, at least or exactly or at most 1366, at least or exactly or atmost 1367, at least or exactly or at most 1368, at least or exactly orat most 1369, at least or exactly or at most 1370, at least or exactlyor at most 1371, at least or exactly or at most 1372, at least orexactly or at most 1373, at least or exactly or at most 1374, at leastor exactly or at most 1375, at least or exactly or at most 1376, atleast or exactly or at most 1377, at least or exactly or at most 1378,at least or exactly or at most 1379, at least or exactly or at most1380, at least or exactly or at most 1381, at least or exactly or atmost 1382, at least or exactly or at most 1383, at least or exactly orat most 1384, at least or exactly or at most 1385, at least or exactlyor at most 1386, at least or exactly or at most 1387, at least orexactly or at most 1388, at least or exactly or at most 1389, at leastor exactly or at most 1390, at least or exactly or at most 1391, atleast or exactly or at most 1392, at least or exactly or at most 1393,at least or exactly or at most 1394, at least or exactly or at most1395, at least or exactly or at most 1396, at least or exactly or atmost 1397, at least or exactly or at most 1398, at least or exactly orat most 1399, at least or exactly or at most 1400, at least or exactlyor at most 1401, at least or exactly or at most 1402, at least orexactly or at most 1403, at least or exactly or at most 1404, at leastor exactly or at most 1405, at least or exactly or at most 1406, atleast or exactly or at most 1407, at least or exactly or at most 1408,at least or exactly or at most 1409, at least or exactly or at most1410, or at least or exactly or at most 1411 contiguous amino acidresidues.

Insofar as embodiment b relates to SEQ ID NO: 94, the at least 5contiguous amino acids referred to in option b) in the definition of thefirst aspect of the invention may also constitute at least or exactly orat most 1412, at least or exactly or at most 1413, at least or exactlyor at most 1414, at least or exactly or at most 1415, at least orexactly or at most 1416, at least or exactly or at most 1417, at leastor exactly or at most 1418, at least or exactly or at most 1419, atleast or exactly or at most 1420, at least or exactly or at most 1421,at least or exactly or at most 1422, at least or exactly or at most1423, at least or exactly or at most 1424, at least or exactly or atmost 1425, at least or exactly or at most 1426, at least or exactly orat most 1427, at least or exactly or at most 1428, at least or exactlyor at most 1429, at least or exactly or at most 1430, at least orexactly or at most 1431, at least or exactly or at most 1432, at leastor exactly or at most 1433, at least or exactly or at most 1434, atleast or exactly or at most 1435, at least or exactly or at most 1436,at least or exactly or at most 1437, at least or exactly or at most1438, at least or exactly or at most 1439, at least or exactly or atmost 1440, at least or exactly or at most 1441, at least or exactly orat most 1442, at least or exactly or at most 1443, at least or exactlyor at most 1444, at least or exactly or at most 1445, at least orexactly or at most 1446, at least or exactly or at most 1447, at leastor exactly or at most 1448, at least or exactly or at most 1449, atleast or exactly or at most 1450, at least or exactly or at most 1451,at least or exactly or at most 1452, at least or exactly or at most1453, at least or exactly or at most 1454, at least or exactly or atmost 1455, at least or exactly or at most 1456, at least or exactly orat most 1457, at least or exactly or at most 1458, at least or exactlyor at most 1459, at least or exactly or at most 1460, at least orexactly or at most 1461, at least or exactly or at most 1462, at leastor exactly or at most 1463, at least or exactly or at most 1464, atleast or exactly or at most 1465, at least or exactly or at most 1466,at least or exactly or at most 1467, at least or exactly or at most1468, at least or exactly or at most 1469, at least or exactly or atmost 1470, at least or exactly or at most 1471, at least or exactly orat most 1472, at least or exactly or at most 1473, at least or exactlyor at most 1474, at least or exactly or at most 1475, at least orexactly or at most 1476, at least or exactly or at most 1477, at leastor exactly or at most 1478, at least or exactly or at most 1479, atleast or exactly or at most 1480, at least or exactly or at most 1481,at least or exactly or at most 1482, at least or exactly or at most1483, at least or exactly or at most 1484, at least or exactly or atmost 1485, at least or exactly or at most 1486, at least or exactly orat most 1487, at least or exactly or at most 1488, at least or exactlyor at most 1489, at least or exactly or at most 1490, at least orexactly or at most 1491, at least or exactly or at most 1492, at leastor exactly or at most 1493, at least or exactly or at most 1494, atleast or exactly or at most 1495, at least or exactly or at most 1496,at least or exactly or at most 1497, at least or exactly or at most1498, at least or exactly or at most 1499, at least or exactly or atmost 1500, at least or exactly or at most 1501, at least or exactly orat most 1502, at least or exactly or at most 1503, at least or exactlyor at most 1504, at least or exactly or at most 1505, at least orexactly or at most 1506, at least or exactly or at most 1507, at leastor exactly or at most 1508, at least or exactly or at most 1509, atleast or exactly or at most 1510, at least or exactly or at most 1511,at least or exactly or at most 1512, at least or exactly or at most1513, at least or exactly or at most 1514, at least or exactly or atmost 1515, at least or exactly or at most 1516, at least or exactly orat most 1517, at least or exactly or at most 1518, at least or exactlyor at most 1519, at least or exactly or at most 1520, at least orexactly or at most 1521, at least or exactly or at most 1522, at leastor exactly or at most 1523, at least or exactly or at most 1524, atleast or exactly or at most 1525, at least or exactly or at most 1526,at least or exactly or at most 1527, at least or exactly or at most1528, at least or exactly or at most 1529, at least or exactly or atmost 1530, at least or exactly or at most 1531, at least or exactly orat most 1532, at least or exactly or at most 1533, at least or exactlyor at most 1534, at least or exactly or at most 1535, at least orexactly or at most 1536, at least or exactly or at most 1537, at leastor exactly or at most 1538, at least or exactly or at most 1539, atleast or exactly or at most 1540, at least or exactly or at most 1541,at least or exactly or at most 1542, at least or exactly or at most1543, at least or exactly or at most 1544, at least or exactly or atmost 1545, at least or exactly or at most 1546, at least or exactly orat most 1547, at least or exactly or at most 1548, at least or exactlyor at most 1549, at least or exactly or at most 1550, at least orexactly or at most 1551, at least or exactly or at most 1552, at leastor exactly or at most 1553, at least or exactly or at most 1554, atleast or exactly or at most 1555, at least or exactly or at most 1556,at least or exactly or at most 1557, at least or exactly or at most1558, at least or exactly or at most 1559, at least or exactly or atmost 1560, at least or exactly or at most 1561, at least or exactly orat most 1562, at least or exactly or at most 1563, at least or exactlyor at most 1564, at least or exactly or at most 1565, at least orexactly or at most 1566, at least or exactly or at most 1567, at leastor exactly or at most 1568, at least or exactly or at most 1569, atleast or exactly or at most 1570, at least or exactly or at most 1571,at least or exactly or at most 1572, at least or exactly or at most1573, at least or exactly or at most 1574, at least or exactly or atmost 1575, at least or exactly or at most 1576, at least or exactly orat most 1577, at least or exactly or at most 1578, at least or exactlyor at most 1579, at least or exactly or at most 1580, at least orexactly or at most 1581, at least or exactly or at most 1582, at leastor exactly or at most 1583, at least or exactly or at most 1584, atleast or exactly or at most 1585, at least or exactly or at most 1586,at least or exactly or at most 1587, at least or exactly or at most1588, at least or exactly or at most 1589, at least or exactly or atmost 1590, at least or exactly or at most 1591, at least or exactly orat most 1592, at least or exactly or at most 1593, at least or exactlyor at most 1594, at least or exactly or at most 1595, at least orexactly or at most 1596, at least or exactly or at most 1597, at leastor exactly or at most 1598, at least or exactly or at most 1599, atleast or exactly or at most 1600, at least or exactly or at most 1601,at least or exactly or at most 1602, at least or exactly or at most1603, at least or exactly or at most 1604, at least or exactly or atmost 1605, at least or exactly or at most 1606, at least or exactly orat most 1607, at least or exactly or at most 1608, at least or exactlyor at most 1609, at least or exactly or at most 1610, at least orexactly or at most 1611, at least or exactly or at most 1612, at leastor exactly or at most 1613, at least or exactly or at most 1614, atleast or exactly or at most 1615, at least or exactly or at most 1616,at least or exactly or at most 1617, at least or exactly or at most1618, at least or exactly or at most 1619, at least or exactly or atmost 1620, at least or exactly or at most 1621, at least or exactly orat most 1622, at least or exactly or at most 1623, at least or exactlyor at most 1624, at least or exactly or at most 1625, at least orexactly or at most 1626, at least or exactly or at most 1627, at leastor exactly or at most 1628, at least or exactly or at most 1629, atleast or exactly or at most 1630, at least or exactly or at most 1631,at least or exactly or at most 1632, at least or exactly or at most1633, at least or exactly or at most 1634, at least or exactly or atmost 1635, at least or exactly or at most 1636, at least or exactly orat most 1637, at least or exactly or at most 1638, at least or exactlyor at most 1639, at least or exactly or at most 1640, at least orexactly or at most 1641, at least or exactly or at most 1642, at leastor exactly or at most 1643, at least or exactly or at most 1644, atleast or exactly or at most 1645, at least or exactly or at most 1646,at least or exactly or at most 1647, at least or exactly or at most1648, at least or exactly or at most 1649 amino acid residues.

In some embodiments the invention relates to a polypeptide comprising anamino acid sequence consisting of at most 5 contiguous amino acidresidues from any one of SEQ ID NOs 1-30. In these embodiment, the atmost 5 contiguous amino acids can, for example, constitute 2, 3, 4contiguous amino acid residues; preferably 4 contiguous amino acids.

In some embodiments, the polypeptide of the invention also has asequence identity with the amino acid sequence of a) defined above of atleast 65%, such as at least 70%, at least 75%, at least 80%, at least85%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, and atleast 99%. Similarly, the polypeptide of the invention in someembodiments also has a sequence identity with the amino acid sequence ofb) defined above of at least 60%, such as at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, and at least 99%.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39, 40, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74,75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, and 90 inany one of SEQ NOs: 1-30, 93, and 94, if the length of the at least orexactly or at most 5 amino acid residues so permits—the N-terminal firstresidue will not be higher numbered than N−L+1, where N is the number ofamino acid residues of the reference sequence and L is the number ofamino acids defined for option b.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104,105, 106, 107, 108, 109, 110, 111, 112, and 113 in any on of SEQ ID NOs:2-30, 93, and 94, if the length of the at least or exactly or at most 5amino acid residues so permits—the N-terminal first residue will not behigher numbered than N−L+1, where N is the number of amino acid residuesof the reference sequence and L is the number of amino acids defined foroption b.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 114 and 115 in any one of SEQ ID NOs: 3-30, 93, and 94, if thelength of the at least or exactly or at most 5 amino acid residues sopermits—the N-terminal first residue will not be higher numbered thanN−L+1, where N is the number of amino acid residues of the referencesequence and L is the number of amino acids defined for option b.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to amino acid residue116 in any one of SEQ ID NOs: 4-30, 93, and 94, if the length of the atleast or exactly or at most 5 amino acid residues so permits—theN-terminal first residue will not be higher numbered than N−L+1, where Nis the number of amino acid residues of the reference sequence and L isthe number of amino acids defined for option b.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any amino acidresidue 117 in any one of SEQ ID NOs: 5-30, 93, and 94, if the length ofthe at least or exactly or at most 5 amino acid residues so permits—theN-terminal first residue will not be higher numbered than N−L+1, where Nis the number of amino acid residues of the reference sequence and L isthe number of amino acids defined for option b.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to amino acid residue118 in any one of SEQ ID NOs: 6-30, 93, and 94, if the length of the atleast or exactly or at most 5 amino acid residues so permits—theN-terminal first residue will not be higher numbered than N−L+1, where Nis the number of amino acid residues of the reference sequence and L isthe number of amino acids defined for option b.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130,131, 132, 133, 134, 135, 136, and 137 in any one of SEQ ID NOs: 7-30,93, and 94, if the length of the at least or exactly or at most 5 aminoacid residues so permits—the N-terminal first residue will not be highernumbered than N−L+1, where N is the number of amino acid residues of thereference sequence and L is the number of amino acids defined for optionb.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 138, 139, 140, 141, 142, 143, 144, 145, 146, and 147 in any oneof SEQ ID NOs: 8-30, 93, and 94, if the length of the at least orexactly or at most 5 amino acid residues so permits—the N-terminal firstresidue will not be higher numbered than N−L+1, where N is the number ofamino acid residues of the reference sequence and L is the number ofamino acids defined for option b.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159,160, 161, 162, 163, and 164 in any one of SEQ ID NOs: 9-30, 93, and 94,if the length of the at least or exactly or at most 5 amino acidresidues so permits—the N-terminal first residue will not be highernumbered than N−L+1, where N is the number of amino acid residues of thereference sequence and L is the number of amino acids defined for optionb.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176,177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190,191, or 192 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204,205, 206, 207, or 208 209, 210, 211, 212, 213, 214, 215, 216, 217, 218,219, 220, 221, 222, 223, 224, and 225 in any one of SEQ ID NOs: 10-30,93, and 94, if the length of the at least or exactly or at most 5 aminoacid residues so permits—the N-terminal first residue will not be highernumbered than N−L+1, where N is the number of amino acid residues of thereference sequence and L is the number of amino acids defined for optionb.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237,238, 239, 240, and 241 and 318 in any one of SEQ ID NOs: 11-30, 93 and94 if the length of the at least or exactly or at most 5 amino acidresidues so permits—the N-terminal first residue will not be highernumbered than N−L+1, where N is the number of amino acid residues of thereference sequence and L is the number of amino acids defined for optionb.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253,254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267,268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281,282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295,296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309,310, 311, 312, 313, 314, 315, 316, 317, and 318 in any one of SEQ IDNOs: 11-30 and 94, if the length of the at least or exactly or at most 5amino acid residues so permits—the N-terminal first residue will not behigher numbered than N−L+1, where N is the number of amino acid residuesof the reference sequence and L is the number of amino acids defined foroption b.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330,331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344,345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, or 356 357, 358,359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, and 372in any one of SEQ ID NOs: 12-30 and 94, if the length of the at least orexactly or at most 5 amino acid residues so permits—the N-terminal firstresidue will not be higher numbered than N−L+1, where N is the number ofamino acid residues of the reference sequence and L is the number ofamino acids defined for option b.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 373, 374, 375, 376, 377, and 378 in any one of SEQ ID NOs:13-30 and 94, if the length of the at least or exactly or at most 5amino acid residues so permits—the N-terminal first residue will not behigher numbered than N−L+1, where N is the number of amino acid residuesof the reference sequence and L is the number of amino acids defined foroption b.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390,391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404,405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418,419, 420, 421, 422, 423, and 424 in any one of SEQ ID NOs: 14-30 and 94,if the length of the at least or exactly or at most 5 amino acidresidues so permits—the N-terminal first residue will not be highernumbered than N−L+1, where N is the number of amino acid residues of thereference sequence and L is the number of amino acids defined for optionb.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, and437 in any one of SEQ ID NOs: 15-30 and 94, if the length of the atleast or exactly or at most 5 amino acid residues so permits—theN-terminal first residue will not be higher numbered than N−L+1, where Nis the number of amino acid residues of the reference sequence and L isthe number of amino acids defined for option b.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449,450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463,464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477,478, 479, and 480 in any one of SEQ NOs: 16-30 and 94, if the length ofthe at least or exactly or at most 5 amino acid residues so permits—theN-terminal first residue will not be higher numbered than N−L+1, where Nis the number of amino acid residues of the reference sequence and L isthe number of amino acids defined for option b.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492,493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506,507, 508 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520,521, 522, 523, 524, 525, 526, 527, 528, 529, 530, and 531 in any one ofSEQ ID NOs: 17-30 and 94, if the length of the at least or exactly or atmost 5 amino acid residues so permits—the N-terminal first residue willnot be higher numbered than N−L+1, where N is the number of amino acidresidues of the reference sequence and L is the number of amino acidsdefined for option b.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543,544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557,558, 559, 560, 561, 562, or 563, 427564, 565, 566, 567, 568, 569, 570,571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584,585, 586, 587, 588, 589, 590, 591, 592, and 593 in any one of SEQ IDNOs: 18-30 and 94, if the length of the at least or exactly or at most 5amino acid residues so permits—the N-terminal first residue will not behigher numbered than N−L+1, where N is the number of amino acid residuesof the reference sequence and L is the number of amino acids defined foroption b.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605,606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619,and 620 in any one of SEQ ID NOs: 19-30 and 94, if the length of the atleast or exactly or at most 5 amino acid residues so permits—theN-terminal first residue will not be higher numbered than N−L+1, where Nis the number of amino acid residues of the reference sequence and L isthe number of amino acids defined for option b.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632,633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646,647, 648, 649, 650, 651, 652, and 653 in any one of SEQ ID NOs: 20-30and 94, if the length of the at least or exactly or at most 5 amino acidresidues so permits—the N-terminal first residue will not be highernumbered than N−L+1, where N is the number of amino acid residues of thereference sequence and L is the number of amino acids defined for optionb.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665,666, 667, 668, 669, 670, and 671 in any one of SEQ ID NOs: 21-30 and 94,if the length of the at least or exactly or at most 5 amino acidresidues so permits—the N-terminal first residue will not be highernumbered than N−L+1, where N is the number of amino acid residues of thereference sequence and L is the number of amino acids defined for optionb.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683,684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, and 697in any one of SEQ ID NOs: 22-30 and 94, if the length of the at least orexactly or at most 5 amino acid residues so permits—the N-terminal firstresidue will not be higher numbered than N−L+1, where N is the number ofamino acid residues of the reference sequence and L is the number ofamino acids defined for option b.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709,710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723,724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737,738, 739, 740, 741, 742, 743, 744, 745, 746, 747, and 748 in any one ofSEQ ID NOs: 23-30 and 94, if the length of the at least or exactly or atmost 5 amino acid residues so permits—the N-terminal first residue willnot be higher numbered than N−L+1, where N is the number of amino acidresidues of the reference sequence and L is the number of amino acidsdefined for option b.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 749, 750, 751, 752, 753, 754, 755, 756 and 757 in any one ofSEQ ID NOs: 24-30 and 94, if the length of the at least or exactly or atmost 5 amino acid residues so permits—the N-terminal first residue willnot be higher numbered than N−L+1, where N is the number of amino acidresidues of the reference sequence and L is the number of amino acidsdefined for option b.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769,770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783,784, 785 and 786 in any one of SEQ ID NOs: 25-30 and 94, if the lengthof the at least or exactly or at most 5 amino acid residues sopermits—the N-terminal first residue will not be higher numbered thanN−L+1, where N is the number of amino acid residues of the referencesequence and L is the number of amino acids defined for option b.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798,799, 800, 801, 802, 803, 804 and 805 in any one of SEQ ID NOs: 26-30 and94, if the length of the at least or exactly or at most 5 amino acidresidues so permits—the N-terminal first residue will not be highernumbered than N−L+1, where N is the number of amino acid residues of thereference sequence and L is the number of amino acids defined for optionb.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 806, 807, 808, 809, 810, 811, 812, 813, 815, 816, 817, 818,819, 820, 821, 811, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832,833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846,847, 848, 849, 850, 851, 852, 853, 854, 855, 856, 857, 858, 859, 860,861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874,875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888,889, 890, 891 and 892 in any one of SEQ ID NOs: 27-30 and 94, if thelength of the at least or exactly or at most 5 amino acid residues sopermits—the N-terminal first residue will not be higher numbered thanN−L+1, where N is the number of amino acid residues of the referencesequence and L is the number of amino acids defined for option b.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 893, 894, 895, 896, 897, 898, 899, 900, 901, 902, 903, 904,905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918,919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932,933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943, 944, 945, 946,947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960,961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974,975, 976, 977, 978, 979, 980, 981, 982, 983, 984, 985, 986, 987, 988,989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, 1000, 1001, 1002,1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014,1015, 1016, 1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026,1027, 1028, 1029, 1030, 1031, 1032, 1033, 1034, 1035, 1036, 1037, 1038,1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050,1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062,1063, 1064, 1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072 and 1073 inany one of SEQ ID NOs: 28-30 and 94, if the length of the at least orexactly or at most 5 amino acid residues so permits—the N-terminal firstresidue will not be higher numbered than N−L+1, where N is the number ofamino acid residues of the reference sequence and L is the number ofamino acids defined for option b.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 1074, 1075, 1076, 1077, 1078, 1079, 1080, 1081, 1082, 1083,1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095,1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107,1108, 1109, 1110, 1111, 1112, 1113, 1114, 1115, 1116, 1117, 1118, 1119,1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127, 1128, 1129, 1130, 1131,1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143,1144, 1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154 and1155 in any one of SEQ ID NOs: 29-30 and 94, if the length of the atleast or exactly or at most 5 amino acid residues so permits—theN-terminal first residue will not be higher numbered than N−L+1, where Nis the number of amino acid residues of the reference sequence and L isthe number of amino acids defined for option b.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 1156, 1157, 1158, 1159, 1160, 1161, 1162, 1163, 1164, 1165,1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175, 1176, 1177,1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189,1190, 1191, 1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201,1202, 1203, 1204, 1205, 1206, 1207, 1208, 1209, 1210, 1211, 1212, 1213,1214, 1215, 1216, 1217, 1218, 1219, 1220, 1221, 1222, 1223, 1224, 1225,1226, 1227, 1228, 1229, 1230, 1231, 1232, 1233, 1234, 1235, 1236, 1237,1238, 1239, 1240, 1241, 1242, 1243, 1244, 1245, 1246, 1247, 1248, 1249,1250, 1251, 1252, 1253, 1254, 1255, 1256, 1257, 1258, 1259, 1260, 1261,1262, 1263, 1264, 1265, 1266, 1267, 1268, 1269, 1270, 1271, 1272, 1273,1274, 1275, 1276, 1277, 1278, 1279, 1280, 1281, 1282, 1283, 1284, 1285,1286, 1287, 1288, 1289, 1290, 1291, 1292, 1293, 1294, 1295, 1296, 1297,1298, 1299, 1300, 1301, 1302, 1303, 1304, 1305, 1306, 1307, 1308, 1309,1310, 1311, 1312, 1313, 1314, 1315, 1316, 1317, 1318, 1319, 1320, 1321,1322, 1323, 1324, 1325, 1326, 1327, 1328, 1329, 1330, 1331, 1332, 1333,1334, 1335, 1336, 1337, 1338, 1339, 1340, 1341, 1342, 1343, 1344, 1345,1346, 1347, 1348, 1349, 1350, 1351, 1352, 1353, 1354, 1355, 1356, 1357,1358, 1359, 1360, 1361, 1362, 1363, 1364, 1365, 1366, 1367, 1368, 1369,1370, 1371, 1372, 1373, 1374, 1375, 1376, 1377, 1378, 1379, 1380, 1381,1382, 1383, 1384, 1385, 1386, 1387, 1388, 1389, 1390, 1391, 1392, 1393,1394, 1395, 1396, 1397, 1398, 1399, 1400, 1401, 1402, 1403, 1404, 1405,1406, 1407, 1408, 1409 and 1410 in SEQ ID NO: 30 or 94, if the length ofthe at least or exactly or at most 5 amino acid residues so permits—theN-terminal first residue will not be higher numbered than N−L+1, where Nis the number of amino acid residues of the reference sequence and L isthe number of amino acids defined for option b.

In the embodiments defined by option b) above, the polypeptide of theinvention is also one that has at least or exactly or at most 5contiguous amino acid residues defined for option b) above and also hasits N-terminal amino acid residue corresponding to any one of amino acidresidues 1408, 1409, 1410, 1411, 1412, 1413, 1414, 1415, 1416, 1417,1418, 1419, 1420, 1421, 1422, 1423, 1424, 1425, 1426, 1427, 1428, 1429,1430, 1431, 1432, 1433, 1434, 1435, 1436, 1437, 1438, 1439, 1440, 1441,1442, 1443, 1444, 1445, 1446, 1447, 1448, 1449, 1450, 1451, 1452, 1453,1454, 1455, 1456, 1457, 1458, 1459, 1460, 1461, 1462, 1463, 1464, 1465,1466, 1467, 1468, 1469, 1470, 1471, 1472, 1473, 1474, 1475, 1476, 1477,1478, 1479, 1480, 1481, 1482, 1483, 1484, 1485, 1486, 1487, 1488, 1489,1490, 1491, 1492, 1493, 1494, 1495, 1496, 1497, 1498, 1499, 1500, 1501,1502, 1503, 1504, 1505, 1506, 1507, 1508, 1509, 1510, 1511, 1512, 1513,1514, 1515, 1516, 1517, 1518, 1519, 1520, 1521, 1522, 1523, 1524, 1525,1526, 1527, 1528, 1529, 1530, 1531, 1532, 1533, 1534, 1535, 1536, 1537,1538, 1539, 1540, 1541, 1542, 1543, 1544, 1545, 1546, 1547, 1548, 1549,1550, 1551, 1552, 1553, 1554, 1555, 1556, 1557, 1558, 1559, 1560, 1561,1562, 1563, 1564, 1565, 1566, 1567, 1568, 1569, 1570, 1571, 1572, 1573,1574, 1575, 1576, 1577, 1578, 1579, 1580, 1581, 1582, 1583, 1584, 1585,1586, 1587, 1588, 1589, 1590, 1591, 1592, 1593, 1594, 1595, 1596, 1597,1598, 1599, 1600, 1601, 1602, 1603, 1604, 1605, 1606, 1607, 1608, 1609,1610, 1611, 1612, 1613, 1614, 1615, 1616, 1617, 1618, 1619, 1620, 1621,1622, 1623, 1624, 1625, 1626, 1627, 1628, 1629, 1630, 1631, 1632, 1633,1634, 1635, 1636, 1637, 1638, 1639, 1640, 1641, 1642, 1643, 1644, and1645 in SEQ ID NO: 94, if the length of the at least or exactly or atmost 5 amino acid residues so permits—the N-terminal first residue willnot be higher numbered than N−L+1, where N is the number of amino acidresidues of the reference sequence and L is the number of amino acidsdefined for option b.

The polypeptide of the invention is in certain embodiments also fused orconjugated to an immunogenic carrier molecule; or, phrased otherwise,the polypeptide of the invention also includes such an immunogeniccarrier molecule in addition to the material derived from SEQ ID NOs:1-30. The immunogenic carrier molecule is a typically polypeptide thatinduces T-helper lymphocyte responses in a majority of humans, such asimmunogenic carrier proteins selected from the group consisting ofkeyhole limpet hemocyanino or a fragment thereof, tetanus toxoid or afragment thereof, diphtheria toxoid or a fragment thereof. Othersuitable carrier molecules are discussed infra. One further fusionpartner which is preferably incorporated is a “His tag”, i.e. a stretchof amino acids, which is rich in or only consists of histidinyl residuesso as to facilitate protein purification.

In preferred embodiments, the polypeptide of the invention detailedabove is capable of inducing an adaptive immune response against thepolypeptide in a mammal, in particular in a human being. Preferably, theadaptive immune response is a protective adaptive immune responseagainst infection with K. pneumoniae. The polypeptide may in these casesinduce a humeral and/or a cellular immune response.

A particularly preferred polypeptide of the invention is derived fromSEQ ID NO: 6 and is otherwise as defined above.

Epitopes

SEQ ID NOs: 1-30 include antigenic determinants (epitopes) that are assuch recognized by antibodies and/or when bound to MHC molecules byT-cell receptors. For the purposes of the present invention, B-cellepitopes (i.e. antibody binding epitopes) are of particular relevance.

It is relatively uncomplicated to identify linear B-cell epitopes—onevery simple approach entails that antibodies raised agains K. pneumoniaeor K. pneumoniae derived proteins disclosed herein are tested forbinding to overlapping oligomeric peptides derived from any one of SEQID NO: 1-30. Thereby, the regions of the K. pneumoniae polypeptide whichare responsible for or contribute to binding to the antibodies can beidentified.

Alternatively, or additionally, one can produce mutated versions of thepolypeptides of the invention, e.g. version where each singlenon-alanine residue in any one of SEQ ID NOs: 1-30 are point mutated toalanine—this method also assists in identifying complex assembled B-cellepitopes; this is the case when binding of the same antibody is modifiedby exchanging amino acids in different areas of the full-lengthpolypeptide.

Also, in silico methods for B-cell epitope prediction can be employed:useful state-of-the-art systems for β-turn prediction is provided inPetersen B et al. (November 2010), Plos One 5(11): e15079; prediction oflinear B-cell epitopes, cf: Larsen J E P et al. (April 2006), ImmunomeResearch, 2:2; prediction of solvent exposed amino acids: Petersen B etal (July 2009), BMC Structural Biology, 9:51.

The Nucleic Acid Fragments of the Invention

The nucleic acid fragment of the invention referred to above ispreferably is a DNA fragment (of a sequence such as SEQ ID NOs: 31-60and 95-98) or an RNA fragment (of a sequence such as SEQ ID NOs 61-90and 99-102).

In some embodiments the at least or exactly 10 consecutive nucleotidesreferred to in option iii) in the definition of the second aspectconsists of at least or exactly 10, such as at least or exactly or atmost 11, such as at least or exactly or at most 12, at least or exactlyor at most 13, at least or exactly or at most 14, at least or exactly orat most 15, at least or exactly or at most 16, at least or exactly or atmost 17 at least or exactly or at most 18, at least or exactly or atmost 19, at least or exactly or at most 20, at least or exactly or atmost 21, at least or exactly or at most 22, at least or exactly or atmost 23, at least or exactly or at most 24, at least or exactly or atmost 25, at least or exactly or at most 26, at least or exactly or atmost 27, at least or exactly or at most 28, at least or exactly or atmost 29, at least or exactly or at most 30, at least or exactly or atmost 31, at least or exactly or at most 32, at least or exactly or atmost 33, at least or exactly or at most 34, at least or exactly or atmost 35, at least or exactly or at most 36, at least or exactly or atmost 37, at least or exactly or at most 38, at least or exactly or atmost 39, at least or exactly or at most 40, at least or exactly or atmost 41, at least or exactly or at most 42, at least or exactly or atmost 43, at least or exactly or at most 44, at least or exactly or atmost 45, at least or exactly or at most 46, at least or exactly or atmost 47, at least or exactly or at most 48, at least or exactly or atmost 49, at least or exactly or at most 50, at least or exactly or atmost 51, at least or exactly or at most 52, at least or exactly or atmost 53, at least or exactly or at most 54, at least or exactly or atmost 55, at least or exactly or at most 56, at least or exactly or atmost 57, at least or exactly or at most 58, at least or exactly or atmost 59, at least or exactly or at most 60, at least or exactly or atmost 61, at least or exactly or at most 62, at least or exactly or atmost 63, at least or exactly or at most 64, at least or exactly or atmost 65, at least or exactly or at most 66, at least or exactly or atmost 67, at least or exactly or at most 68, at least or exactly or atmost 69, at least or exactly or at most 70, at least or exactly or atmost 71, at least or exactly or at most 72, at least or exactly or atmost 73, at least or exactly or at most 74, at least or exactly or atmost 75, at least or exactly or at most 76, at least or exactly or atmost 77, at least or exactly or at most 78, at least or exactly or atmost 79, at least or exactly or at most 80, at least or exactly or atmost 81, at least or exactly or at most 82, at least or exactly or atmost 83, at least or exactly or at most 84, at least or exactly or atmost 85, at least or exactly or at most 86, at least or exactly or atmost 87, at least or exactly or at most 88, at least or exactly or atmost 89, at least or exactly or at most 90, at least or exactly or atmost 91, at least or exactly or at most 92, at least or exactly or atmost 93, at least or exactly or at most 94, at least or exactly or atmost 95, at least or exactly or at most 96, at least or exactly or atmost 97, at least or exactly or at most 98, at least or exactly or atmost 99, at least or exactly or at most 100, at least or exactly or atmost 101, at least or exactly or at most 102, at least or exactly or atmost 103, at least or exactly or at most 104, at least or exactly or atmost 105, at least or exactly or at most 106, at least or exactly or atmost 107, at least or exactly or at most 108, at least or exactly or atmost 109, at least or exactly or at most 110, at least or exactly or atmost 111, at least or exactly or at most 112, at least or exactly or atmost 113, at least or exactly or at most 114, at least or exactly or atmost 115, at least or exactly or at most 116, at least or exactly or atmost 117, at least or exactly or at most 118, at least or exactly or atmost 119, at least or exactly or at most 120, at least or exactly or atmost 121, at least or exactly or at most 122, at least or exactly or atmost 123, at least or exactly or at most 124, at least or exactly or atmost 125, at least or exactly or at most 126, at least or exactly or atmost 127, at least or exactly or at most 128, at least or exactly or atmost 129, at least or exactly or at most 130, at least or exactly or atmost 131, at least or exactly or at most 132, at least or exactly or atmost 133, at least or exactly or at most 134, at least or exactly or atmost 135, at least or exactly or at most 136, at least or exactly or atmost 137, at least or exactly or at most 138, at least or exactly or atmost 139, at least or exactly or at most 140, at least or exactly or atmost 141, at least or exactly or at most 142, at least or exactly or atmost 143, at least or exactly or at most 144, at least or exactly or atmost 145, at least or exactly or at most 146, at least or exactly or atmost 147, at least or exactly or at most 148, at least or exactly or atmost 149, at least or exactly or at most 150, at least or exactly or atmost 151, at least or exactly or at most 152, at least or exactly or atmost 153, at least or exactly or at most 154, at least or exactly or atmost 155, at least or exactly or at most 156, at least or exactly or atmost 157, at least or exactly or at most 158, at least or exactly or atmost 159, at least or exactly or at most 160, at least or exactly or atmost 171, at least or exactly or at most 172, at least or exactly or atmost 173, at least or exactly or at most 174, at least or exactly or atmost 175, at least or exactly or at most 176, at least or exactly or atmost 177, at least or exactly or at most 178, at least or exactly or atmost 179, at least or exactly or at most 180, at least or exactly or atmost 181, at least or exactly or at most 182, at least or exactly or atmost 183, at least or exactly or at most 184, at least or exactly or atmost 185, at least or exactly or at most 186, at least or exactly or atmost 187, at least or exactly or at most 188, at least or exactly or atmost 189, at least or exactly or at most 190, at least or exactly or atmost 191, at least or exactly or at most 192, at least or exactly or atmost 193, at least or exactly or at most 194, at least or exactly or atmost 195, at least or exactly or at most 196, at least or exactly or atmost 197, at least or exactly or at most 198, at least or exactly or atmost 199, at least or exactly or at most 200, at least or exactly or atmost 201, at least or exactly or at most 202, at least or exactly or atmost 203, at least or exactly or at most 204, at least or exactly or atmost 205, at least or exactly or at most 206, at least or exactly or atmost 207, at least or exactly or at most 208, at least or exactly or atmost 209, at least or exactly or at most 210, at least or exactly or atmost 211, at least or exactly or at most 212, at least or exactly or atmost 213, at least or exactly or at most 214, at least or exactly or atmost 215, at least or exactly or at most 216, at least or exactly or atmost 217, at least or exactly or at most 218, at least or exactly or atmost 219, at least or exactly or at most 220, at least or exactly or atmost 221, at least or exactly or at most 222, at least or exactly or atmost 223, at least or exactly or at most 224, at least or exactly or atmost 225, at least or exactly or at most 226, at least or exactly or atmost 227, at least or exactly or at most 228, at least or exactly or atmost 229, at least or exactly or at most 230, at least or exactly or atmost 231, at least or exactly or at most 232, at least or exactly or atmost 233, at least or exactly or at most 234, at least or exactly or atmost 235, at least or exactly or at most 236, at least or exactly or atmost 237, at least or exactly or at most 238, at least or exactly or atmost 239, at least or exactly or at most 240, at least or exactly or atmost 241, at least or exactly or at most 242, at least or exactly or atmost 243, at least or exactly or at most 244, at least or exactly or atmost 245, at least or exactly or at most 246, at least or exactly or atmost 247, at least or exactly or at most 248, at least or exactly or atmost 249, at least or exactly or at most 250, at least or exactly or atmost 251, at least or exactly or at most 252, at least or exactly or atmost 253, at least or exactly or at most 254, at least or exactly or atmost 255, at least or exactly or at most 256, at least or exactly or atmost 257, at least or exactly or at most 258, at least or exactly or atmost 259, at least or exactly or at most 260, at least or exactly or atmost 271, at least or exactly or at most 272, at least or exactly or atmost 273, at least or exactly or at most 274, at least or exactly or atmost 275, at least or exactly or at most 276, at least or exactly or atmost 277, at least or exactly or at most 278, at least or exactly or atmost 279, at least or exactly or at most 280, at least or exactly or atmost 281, at least or exactly or at most 282, at least or exactly or atmost 283, at least or exactly or at most 284, and at least or exactly orat most 285 consecutive nucleotides in any one of SEQ ID NOs:31-60.Longer fragments are contemplated, i.e. fragments having at least 200,at least 300 at least 400, at least 500, at least 600, at least 700, atleast 800, at least 900, at least 1000, at least 1500, at least 2000, atleast 2500, at least 3000, at least 3500, and at least 4000 consecutivenucleotides from those of SEQ ID NOs: 31-90 and 95-102 that encompassfragments of such lengths.

In some embodiments the at most 10 consecutive nucleotides referred toin option iii) in the definition of the second aspect of the inventionconstitute 6, 7, 8, 9 or 10 nucleotides.

The nucleic acid fragment of the invention discussed above typically hasa sequence identity with the nucleotide sequence defined for i) or ii)above, which is at least 65%, such as at least 70%, at least 75%, atleast 80%, at least 85%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, and at least 99%.

The nucleic acid fragment of the invention discussed above may also havea sequence identity with the nucleotide sequence defined for iii) above,which is at least 65%, such as at least 70%, at least 75%, at least 80%,at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, andat least 99%.

The nucleic acid fragment of the invention described above comprises incertain embodiments at least or exactly or at most X distinct nucleicacid sequences each encoding a polypeptide of the invention, where eachof said X distinct nucleic acid sequences encodes at least or exactly orat most one immunogenic amino acid sequence present in or derived fromany one of SEQ ID NOs: 1-30 and wherein said X distinct nucleic acidsequences together encode immunogenic amino acid sequences present in orderived from at least or exactly or at most X of SEQ ID NOs: 1-30, 93 or94, wherein X is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, and 32. In other words, such a nucleic acid fragment encodesseveral polypeptides of the invention. In some embodiments, the Xnucleic acid sequences are expressed as separate encoded proteins and inother embodiments as “pearls on a string”, i.e. fused proteins. In someembodiments, immunogenic amino acid sequences from any one of SEQ IDNOs: 1-30, 93 and 94 are only present in one of said X nucleic acidsequences.

It will be understood that the nucleic acid fragments of the inventionmay be used for both production, carrier and vaccine purposes—the latterwill require that the sequences are included in expression vectors thatmay lead to production of immunogenic proteins in the host animalreceiving the vector.

The Vectors of the Invention

Vectors of the invention fall into several categories discussed infra.One preferred vector of the invention comprises in operable linkage andin the 5′-3′ direction, an expression control region comprising anenhancer/promoter for driving expression of the nucleic acid fragmentdefined for option i) above, optionally a signal peptide codingsequence, a nucleotide sequence defined for option i), and optionally aterminator. Hence, such a vector constitutes an expression vector usefulfor effecting production in cells of the polypeptide of the invention.Since the polypeptides of the invention are bacterial of organ,recombinant production is conveniently effected in bacterial host cells,so here it is preferred that the expression control region drivesexpression in prokaryotic cell such as a bacterium, e.g. in E coli.However, if the vector is to drive expression in mammalian cell (aswould be the case for a DNA vaccine vector), the expression controlregion should be adapted to this particular use.

At any rate, certain vectors of the invention are capable of autonomousreplication.

Also, the vector of the invention may be one that is capable of beingintegrated into the genome of a host cell—this is particularly useful ifthe vector is use in the production of stably transformed cells, wherethe progeny will also include the genetic information introduced via thevector. Alternatively, vectors incapable of being integrated into thegenome of a mammalian host cell are useful in e.g. DNA vaccination.

Typically, the vector of the invention is selected from the groupconsisting of a virus, such as a attenuated virus (which may in itselfbe useful as a vaccine agent), a bacteriophage, a plasmid, aminichromosome, and a cosmid.

Particularly interesting vectors are viral vectors (in particular thoseuseful as vaccine agents). These may be selected from the groupconsisting of a retrovirus vector, such as a lentivirus vector, anadenovirus vector, an adeno-associated virus vector, and a pox virusvector. Certain pox virus vectors are preferred, in particular vacciniavirus vectors. A particularly preferred vaccinia virus vector is amodified vaccinia Ankara (MVA) vector.

A more detailed discussion of vectors of the invention is provided inthe following:

Polypeptides of the invention may be encoded by a nucleic acid moleculecomprised in a vector. A nucleic acid sequence can be “heterologous,”which means that it is in a context foreign to the cell in which thevector is being introduced, which includes a sequence homologous to asequence in the cell but in a position within the host cell where it isordinarily not found. Vectors include naked DNAs, RNAs, plasmids,cosmids, viruses (bacteriophage, animal viruses, and plant viruses), andartificial chromosomes (e.g., YACs). One of skill in the art would bewell equipped to construct a vector through standard recombinanttechniques (for example Sambrook et al, 2001; Ausubel et al, 1996, bothincorporated herein by reference). In addition to encoding thepolypeptides of this invention, a vector of the present invention mayencode polypeptide sequences such as a tag or immunogenicity enhancingpeptide (e.g. an immunogenic carrier or a fusion partner that stimulatesthe immune system, such as a cytokine or active fragment thereof).Useful vectors encoding such fusion proteins include pIN vectors (Inouyeet al, 1985), vectors encoding a stretch of histidines, and pGEXvectors, for use in generating glutathione S-transferase (GST) solublefusion proteins for later purification and separation or cleavage.

Vectors of the invention may be used in a host cell to produce apolypeptide of the invention that may subsequently be purified foradministration to a subject or the vector may be purified for directadministration to a subject for expression of the protein in the subject(as is the case when administering a nucleic acid vaccine).

Expression vectors can contain a variety of “control sequences,” whichrefer to nucleic acid sequences necessary for the transcription andpossibly translation of an operably linked coding sequence in aparticular host organism. In addition to control sequences that governtranscription and translation, vectors and expression vectors maycontain nucleic acid sequences that serve other functions as well andare described infra.

1. Promoters and Enhancers

A “promoter” is a control sequence. The promoter is typically a regionof a nucleic acid sequence at which initiation and rate of transcriptionare controlled. It may contain genetic elements at which regulatoryproteins and molecules may bind such as RNA polymerase and othertranscription factors. The phrases “operatively positioned,”“operatively linked,” “under control,” and “under transcriptionalcontrol” mean that a promoter is in a correct functional location and/ororientation in relation to a nucleic acid sequence to controltranscriptional initiation and expression of that sequence. A promotermay or may not be used in conjunction with an “enhancer,” which refersto a cis-acting regulatory sequence involved in the transcriptionalactivation of a nucleic acid sequence.

A promoter may be one naturally associated with a gene or sequence, asmay be obtained by isolating the 5′ non-coding sequences locatedupstream of the coding segment or exon. Such a promoter can be referredto as “endogenous.” Similarly, an enhancer may be one naturallyassociated with a nucleic acid sequence, located either downstream orupstream of that sequence. Alternatively, certain advantages will begained by positioning the coding nucleic acid segment under the controlof a recombinant or heterologous promoter, which refers to a promoterthat is not normally associated with a nucleic acid sequence in itsnatural environment. A recombinant or heterologous enhancer refers alsoto an enhancer not normally associated with a nucleic acid sequence inits natural state. Such promoters or enhancers may include promoters orenhancers of other genes, and promoters or enhancers isolated from anyother prokaryotic, viral, or eukaryotic cell, and promoters or enhancersnot “naturally occurring,” i.e., containing different elements ofdifferent transcriptional regulatory regions, and/or mutations thatalter expression. In addition to producing nucleic acid sequences ofpromoters and enhancers synthetically, sequences may be produced usingrecombinant cloning and/or nucleic acid amplification technology,including PCR™, in connection with the compositions disclosed herein(see U.S. Pat. Nos. 4,683,202, 5,928,906, each incorporated herein byreference).

Naturally, it may be important to employ a promoter and/or enhancer thateffectively direct(s) the expression of the DNA segment in the cell typeor organism chosen for expression. Those of skill in the art ofmolecular biology generally know the use of promoters, enhancers, andcell type combinations for protein expression (see Sambrook et al, 2001,incorporated herein by reference). The promoters employed may beconstitutive, tissue-specific, or inducible and in certain embodimentsmay direct high level expression of the introduced DNA segment underspecified conditions, such as large-scale production of recombinantproteins or peptides.

Examples of inducible elements, which are regions of a nucleic acidsequence that can be activated in response to a specific stimulus,include but are not limited to Immunoglobulin Heavy Chain (Banerji etal, 1983; Gilles et al, 1983; Grosschedl et al, 1985; Atchinson et al,1986, 1987; toiler et al, 1987; Weinberger et al, 1984; Kiledjian et al,1988; Porton et al; 1990), Immunoglobulin Light Chain (Queen et al,1983; Picard et al, 1984), T Cell Receptor (Luria et al, 1987; Winoto etal, 1989; Redondo et al; 1990), HLA DQα and/or DQβ (Sullivan et al,1987), 13-Interferon (Goodbourn et al, 1986; Fujita et al, 1987;Goodbourn et al, 1988), Interleukin-2 (Greene et al, 1989),Interleukin-2 Receptor (Greene et al, 1989; Lin et al, 1990), MHC ClassII 5 (Koch et al, 1989), MHC Class II HLA-DRα (Sherman et al, 1989),β-Actin (Kawamoto et al, 1988; Ng et al; 1989), Muscle Creatine Kinase(MCK) (Jaynes et al, 1988; Horlick et al, 1989; Johnson et al, 1989),Prealbumin (Transthyretin) (Costa et al, 1988), Elastase I (Omitz et al,1987), Metallothionein (MTII) (Karin et al, 1987; Culotta et al, 1989),Collagenase (Pinkert et al, 1987; Angel et al, 1987), Albumin (Pinkertet al, 1987; Tranche et al, 1989, 1990), α-Fetoprotein (God bout et al,1988; Campere et al, 1989), γ-Globin (Bodine et al, 1987; Perez-Stableet al, 1990), β-Globin (Trudel et al, 1987), c-fos (Cohen et al, 1987),c-HA-ras (Triesman, 1986; Deschamps et al, 1985), Insulin (Edlund et al,1985), Neural Cell Adhesion Molecule (NCAM) (Hirsh et al, 1990),αl-Antitrypain (Larimer et al, 1990), H2B (TH2B) Histone (Hwang et al,1990), Mouse and/or Type I Collagen (Ripe et al, 1989),Glucose-Regulated Proteins (GRP94 and GRP78) (Chang et al, 1989), RatGrowth Hormone (Larsen et al, 1986), Human Serum Amyloid A (SAA)(Edbrooke et al, 1989), Troponin I (TN I) (Yutzey et al, 1989),Platelet-Derived Growth Factor (PDGF) (Pech et al, 1989), DuchenneMuscular Dystrophy (Klamut et al, 1990), SV40 (Banerji et al, 1981;Moreau et al, 1981; Sleigh et al, 1985; Firak et al, 1986; Herr et al,1986; Imbra et al, 1986; Kadesch et al, 1986; Wang et al, 1986; Ondek etal, 1987; Kuhl et al, 1987; Schaffner et al, 1988), Polyoma(Swartzendruber et al, 1975; Vasseur et al, 1980; Katinka et al, 1980,1981; Tyndell et al, 1981; Dandolo et al, 1983; de Villiers et al, 1984;Hen et al, 1986; Satake et al, 1988; Campbell et al, 1988), Retroviruses(Kriegler et al, 1982, 1983; Levinson et al, 1982; Kriegler et al, 1983,1984a, b, 1988; Bosze et al, 1986; Miksicek et al, 1986; Celander et al,1987; Thiesen et al, 1988; Celander et al, 1988; Choi et al, 1988;Reisman et al, 1989), Papilloma Virus (Campo et al, 1983; Lusky et al,1983; Spandidos and Wilkie, 1983; Spalholz et al, 1985; Lusky et al,1986; Cripe et al, 1987; Gloss et al, 1987; Hirochika et al, 1987;Stephens et al, 1987), Hepatitis B Virus (Bulla et al, 1986; Jameel etal, 1986; Shaul et al, 1987; Spandau et al, 1988; Vannice et al, 1988),Human Immunodeficiency Virus (Muesing et al, 1987; Hauber et al, 1988;Jakobovits et al, 1988; Feng et al, 1988; Takebe et al, 1988; Rosen etal, 1988; Berkhout et al, 1989; Laspia et al, 1989; Sharp et al, 1989;Braddock et al, 1989), Cytomegalovirus (CMV) IE (Weber et al, 1984;Boshart et al, 1985; Foecking et al, 1986), Gibbon Ape Leukemia Virus(Holbrook et al, 1987; Quinn et al, 1989).

Inducible Elements include, but are not limited to MT II—Phorbol Ester(TFA)/Heavy metals (Palmiter et al, 1982; Haslinger et al, 1985; Searleet al, 1985; Stuart et al, 1985; Imagawa et al, 1987, Karin et al, 1987;Angel et al, 1987b; McNeall et al, 1989); MMTV (mouse mammary tumorvirus)—Glucocorticoids (Huang et al, 1981; Lee et al, 1981; Majors etal, 1983; Chandler et al, 1983; Lee et al, 1984; Ponta et al, 1985;Sakai et al, 1988); β-Interferon—poly(rl)x/poly(rc) (Tavernier et al,1983); Adenovirus 5 E2—EIA (Imperiale et al, 1984); Collagenase—PhorbolEster (TPA) (Angel et al, 1987a); Stromelysin—Phorbol Ester (TPA) (Angelet al, 1987b); SV40—Phorbol Ester (TPA) (Angel et al, 1987b); Murine MXGene—Interferon, Newcastle Disease Virus (Hug et al, 1988); GRP78Gene—A23187 (Resendez et al, 1988); α-2-Macroglobulin—IL-6 (Kunz et al,1989); Vimentin—Serum (Rittling et al, 1989); MHC Class I Gene H-2Kb—Interferon (Blanar et al, 1989); HSP70—EIA/SV40 Large T Antigen(Taylor et al, 1989, 1990a, 1990b); Proliferin—Phorbol Ester/TPA(Mordacq et al, 1989); Tumor Necrosis Factor—PMA (Hensel et al, 1989);and Thyroid Stimulating HormoneaGene—Thyroid Hormone (Chatterjee et al,1989).

Also contemplated as useful in the present invention are the dectin-1and dectin-2 promoters. Additionally any promoter/enhancer combination(as per the Eukaryotic Promoter Data Base EPDB) could also be used todrive expression of structural genes encoding oligosaccharide processingenzymes, protein folding accessory proteins, selectable marker proteinsor a heterologous protein of interest.

The particular promoter that is employed to control the expression ofpeptide or protein encoding polynucleotide of the invention is notbelieved to be critical, so long as it is capable of expressing thepolynucleotide in a targeted cell, preferably a bacterial cell. Where ahuman cell is targeted, it is preferable to position the polynucleotidecoding region adjacent to and under the control of a promoter that iscapable of being expressed in a human cell. Generally speaking, such apromoter might include either a bacterial, human or viral promoter.

In various embodiments, the human cytomegalovirus (CMV) immediate earlygene promoter, the SV40 early promoter, and the Rous sarcoma virus longterminal repeat can be used to obtain high level expression of a relatedpolynucleotide to this invention. The use of other viral or mammaliancellular or bacterial phage promoters, which are well known in the art,to achieve expression of polynucleotides is contemplated as well.

In embodiments in which a vector is administered to a subject forexpression of the protein, it is contemplated that a desirable promoterfor use with the vector is one that is not down-regulated by cytokinesor one that is strong enough that even if down-regulated, it produces aneffective amount of the protein/polypeptide of the current invention ina subject to elicit an immune response. Non-limiting examples of theseare CMV IE and RSV LTR. In other embodiments, a promoter that isup-regulated in the presence of cytokines is employed. The MHC Ipromoter increases expression in the presence of IFN-γ.

Tissue specific promoters can be used, particularly if expression is incells in which expression of an antigen is desirable, such as dendriticcells or macrophages. The mammalian MHC I and MHC II promoters areexamples of such tissue-specific promoters. 2. Initiation Signals andInternal Ribosome Binding Sites (IRES)

A specific initiation signal also may be required for efficienttranslation of coding sequences. These signals include the ATGinitiation codon or adjacent sequences. Exogenous translational controlsignals, including the ATG initiation codon, may need to be provided.One of ordinary skill in the art would readily be capable of determiningthis and providing the necessary signals. It is well known that theinitiation codon must be “in-frame” with the reading frame of thedesired coding sequence to ensure translation of the entire insert. Theexogenous translational control signals and initiation codons can beeither natural or synthetic and may be operable in bacteria or mammaliancells. The efficiency of expression may be enhanced by the inclusion ofappropriate transcription enhancer elements.

In certain embodiments of the invention, the use of internal ribosomeentry sites (IRES) elements are used to create multigene, orpolycistronic, messages. IRES elements are able to bypass the ribosomescanning model of 5′ methylated Cap dependent translation and begintranslation at internal sites (Pelletier and Sonenberg, 1988). IRESelements from two members of the picornavirus family (polio andencephalomyocarditis) have been described (Pelletier and Sonenberg,1988), as well an IRES from a mammalian message (Macejak and Sarnow,1991). IRES elements can be linked to heterologous open reading frames.Multiple open reading frames can be transcribed together, each separatedby an IRES, creating polycistronic messages. By virtue of the IRESelement, each open reading frame is accessible to ribosomes forefficient translation. Multiple genes can be efficiently expressed usinga single promoter/enhancer to transcribe a single message (see U.S. Pat.Nos. 5,925,565 and 5,935,819, herein incorporated by reference).

2. Multiple Cloning Sites

Vectors can include a multiple cloning site (MCS), which is a nucleicacid region that contains multiple restriction enzyme sites, any ofwhich can be used in conjunction with standard recombinant technology todigest the vector. (See Carbonelli et al, 1999, Levenson et al, 1998,and Cocea, 1997, incorporated herein by reference.) Frequently, a vectoris linearized or fragmented using a restriction enzyme that cuts withinthe MCS to enable exogenous sequences to be ligated to the vector.Techniques involving restriction enzymes and ligation reactions are wellknown to those of skill in the art of recombinant technology.

3. Splicing Sites

Most transcribed eukaryotic RNA molecules will undergo RNA splicing toremove introns from the primary transcripts. If relevant in the contextof vectors of the present invention, vectors containing genomiceukaryotic sequences may require donor and/or acceptor splicing sites toensure proper processing of the transcript for protein expression. (SeeChandler et al, 1997, incorporated herein by reference.)

4. Termination Signals

The vectors or constructs of the present invention will generallycomprise at least one termination signal. A “termination signal” or“terminator” is comprised of the DNA sequences involved in specifictermination of an RNA transcript by an RNA polymerase. Thus, in certainembodiments a termination signal that ends the production of an RNAtranscript is contemplated. A terminator may be necessary in vivo toachieve desirable message levels.

In eukaryotic systems, the terminator region may also comprise specificDNA sequences that permit site-specific cleavage of the new transcriptso as to expose a polyadenylation site. This signals a specializedendogenous polymerase to add a stretch of about 200 A residues (poly A)to the 3′ end of the transcript. RNA molecules modified with this polyAtail appear to more stable and are translated more efficiently. Thus, inother embodiments involving eukaryotes, it is preferred that thatterminator comprises a signal for the cleavage of the RNA, and it ismore preferred that the terminator signal promotes polyadenylation ofthe message.

Terminators contemplated for use in the invention include any knownterminator of transcription described herein or known to one of ordinaryskill in the art, including but not limited to, for example, the bovinegrowth hormone terminator or viral termination sequences, such as theSV40 terminator. In certain embodiments, the termination signal may be alack of transcribable or translatable sequence, such as due to asequence truncation.

5. Polyadenylation Signals

In expression, particularly eukaryotic expression (as is relevant innucleic acid vaccination), one will typically include a polyadenylationsignal to effect proper polyadenylation of the transcript. The nature ofthe polyadenylation signal is not believed to be crucial to thesuccessful practice of the invention, and/or any such sequence may beemployed. Preferred embodiments include the SV40 polyadenylation signaland/or the bovine growth hormone polyadenylation signal, convenientand/or known to function well in various target cells. Polyadenylationmay increase the stability of the transcript or may facilitatecytoplasmic transport.

6. Origins of Replication

In order to propagate a vector in a host cell, it may contain one ormore origins of replication sites (often termed “on”), which is aspecific nucleic acid sequence at which replication is initiated.Alternatively an autonomously replicating sequence (ARS) can be employedif the host cell is yeast.

7. Selectable and Screenable Markers

In certain embodiments of the invention, cells containing a nucleic acidconstruct of the present invention may be identified in vitro or in vivoby encoding a screenable or selectable marker in the expression vector.When transcribed and translated, a marker confers an identifiable changeto the cell permitting easy identification of cells containing theexpression vector. Generally, a selectable marker is one that confers aproperty that allows for selection. A positive selectable marker is onein which the presence of the marker allows for its selection, while anegative selectable marker is one in which its presence prevents itsselection. An example of a positive selectable marker is a drugresistance marker.

Usually the inclusion of a drug selection marker aids in the cloning andidentification of transformants, for example, markers that conferresistance to neomycin, puromycin, hygromycin, DHFR, GPT, zeocin orhistidinol are useful selectable markers. In addition to markersconferring a phenotype that allows for the discrimination oftransformants based on the implementation of conditions, other types ofmarkers including screenable markers such as GFP for colorimetricanalysis. Alternatively, screenable enzymes such as herpes simplex virusthymidine kinase (tk) or chloramphenicol acetyltransferase (CAT) may beutilized. One of skill in the art would also know how to employimmunologic markers that can be used in conjunction with FACS analysis.The marker used is not believed to be important, so long as it iscapable of being expressed simultaneously with the nucleic acid encodinga protein of the invention. Further examples of selectable andscreenable markers are well known to one of skill in the art.

The Transformed Cells of the Invention

Transformed cells of the invention are useful as organisms for producingthe polypeptide of the invention, but also as simple “containers” ofnucleic acids and vectors of the invention.

Certain transformed cells of the invention are capable of replicatingthe nucleic acid fragment defined for option i) of the second aspect ofthe invention. Preferred transformed cells of the invention are capableof expressing the nucleic acid fragment defined for option i).

For recombinant production it is convenient, but not a prerequisite thatthe transformed cell according is prokaryotic, such as a bacterium, butgenerally both prokaryotic cells and eukaryotic cells may be used.

Suitable prokaryotic cells are bacterial cells selected from the groupconsisting of Escherichia (such as E. coli), Bacillus (e.g. Bacillussubtilis), Salmonella, and Mycobacterium (preferably non-pathogenic,e.g. M. bovis BCG).

Eukaryotic cells can be in the form of yeasts (such as Saccharomycescerevisiae) and protozoans. Alternatively, the transformed eukaryoticcells are derived from a multicellular organism such as a fungus, aninsect cell, a plant cell, or a mammalian cell.

For production purposes, it is advantageous that the transformed cell ofthe invention is is stably transformed by having the nucleic aciddefined above for option i) stably integrated into its genome, and incertain embodiments it is also preferred that the transformed cellsecretes or carries on its surface the polypeptide of the invention,since this facilitates recovery of the polypeptides produced. Aparticular version of this embodiment is one where the transformed cellis a bacterium and secretion of the polypeptide of the invention is intothe periplasmic space.

As noted above, stably transformed cells are preferred—these i.a. allowsthat cell lines comprised of transformed cells as defined herein may beestablished—such cell lines are particularly preferred aspects of theinvention.

Further details on cells and cell lines are presented in the following:

Suitable cells for recombinant nucleic acid expression of the nucleicacid fragments of the present invention are prokaryotes and eukaryotes.Examples of prokaryotic cells include E. coli; members of theStaphylococcus genus, such as S. epidermidis; members of theLactobacillus genus, such as L. plantarum; members of the Lactococcusgenus, such as L. lactis; members of the Bacillus genus, such as B.subtilis; members of the Corynebacterium genus such as C. glutamicum;and members of the Pseudomonas genus such as Ps. fluorescens. Examplesof eukaryotic cells include mammalian cells; insect cells; yeast cellssuch as members of the Saccharomyces genus (e.g. S. cerevisiae), membersof the Pichia genus (e.g. P. pastoris), members of the Hansenula genus(e.g. H. polymorpha), members of the Kluyveromyces genus (e.g. K. lactisor K. fragilis) and members of the Schizosaccharomyces genus (e.g. S.pombe).

Techniques for recombinant gene production, introduction into a cell,and recombinant gene expression are well known in the art. Examples ofsuch techniques are provided in references such as Ausubel, CurrentProtocols in Molecular Biology, John Wiley, 1987-2002, and Sambrook etal., Molecular Cloning, A Laboratory Manual, 2 nd Edition, Cold SpringHarbor Laboratory Press, 1989.

As used herein, the terms “cell,” “cell line,” and “cell culture” may beused interchangeably. All of these terms also include their progeny,which is any and all subsequent generations. It is understood that allprogeny may not be identical due to deliberate or inadvertent mutations.In the context of expressing a heterologous nucleic acid sequence, “hostcell” refers to a prokaryotic or eukaryotic cell, and it includes anytransformable organism that is capable of replicating a vector orexpressing a heterologous gene encoded by a vector. A host cell can, andhas been, used as a recipient for vectors or viruses. A host cell may be“transfected” or “transformed,” which refers to a process by whichexogenous nucleic acid, such as a recombinant protein-encoding sequence,is transferred or introduced into the host cell. A transformed cellincludes the primary subject cell and its progeny.

Host cells may be derived from prokaryotes or eukaryotes, includingbacteria, yeast cells, insect cells, and mammalian cells for replicationof the vector or expression of part or all of the nucleic acidsequence(s). Numerous cell lines and cultures are available for use as ahost cell, and they can be obtained through the American Type CultureCollection (ATCC), which is an organization that serves as an archivefor living cultures and genetic materials (www.atcc.orq) or from otherdepository institutions such as Deutsche Sammlung vor Micrroorganismenand Zellkulturen (DSM). An appropriate host can be determined by one ofskill in the art based on the vector backbone and the desired result. Aplasmid or cosmid, for example, can be introduced into a prokaryote hostcell for replication of many vectors or expression of encoded proteins.Bacterial cells used as host cells for vector replication and/orexpression include Staphylococcus strains, DH5a, WI 09, and KCB, as wellas a number of commercially available bacterial hosts such as SURE®Competent Cells and SOLOP ACK™ Gold Cells (STRATAGENE®, La Jolla,Calif.). Alternatively, bacterial cells such as E. coli LE392 could beused as host cells for phage viruses. Appropriate yeast cells includeSaccharomyces cerevisiae, Saccharomyces pombe, and Pichia pastoris.

Examples of eukaryotic host cells for replication and/or expression of avector include HeLa, NIH3T3, Jurkat, 293, Cos, CHO, Saos, and PC12. Manyhost cells from various cell types and organisms are available and wouldbe known to one of skill in the art. Similarly, a viral vector may beused in conjunction with either a eukaryotic or prokaryotic host cell,particularly one that is permissive for replication or expression of thevector.

Some vectors may employ control sequences that allow it to be replicatedand/or expressed in both prokaryotic and eukaryotic cells. One of skillin the art would further understand the conditions under which toincubate all of the above described host cells to maintain them and topermit replication of a vector. Also understood and known are techniquesand conditions that would allow large-scale production of vectors, aswell as production of the nucleic acids encoded by vectors and theircognate polypeptides, proteins, or peptides.

Expression Systems

Numerous expression systems exist that comprise at least a part or allof the compositions discussed above. Prokaryote- and/or eukaryote-basedsystems can be employed for use with the present invention to producenucleic acid sequences, or their cognate polypeptides, proteins andpeptides. Many such systems are commercially and widely available.

The insect cell/baculovirus system can produce a high level of proteinexpression of a heterologous nucleic acid segment, such as described inU.S. Pat. Nos. 5,871,986, 4,879,236, both herein incorporated byreference, and which can be bought, for example, under the name MAXBAC®2.0 from INVITROGEN® and BACPACK™ Baculovirus expression system fromCLONTECH®

In addition to the disclosed expression systems of the invention, otherexamples of expression systems include STRATAGENE®'s COMPLETE CONTROL′″Inducible Mammalian Expression System, which involves a syntheticecdysone-inducible receptor, or its pET Expression System, an E. coliexpression system. Another example of an inducible expression system isavailable from INVITROGEN®, which carries the T-REX™(tetracycline-regulated expression) System, an inducible mammalianexpression system that uses the full-length CMV promoter. INVITROGEN®also provides a yeast expression system called the Pichia methanolicaExpression System, which is designed for high-level production ofrecombinant proteins in the methylotrophic yeast Pichia methanolica. Oneof skill in the art would know how to express a vector, such as anexpression construct, to produce a nucleic acid sequence or its cognatepolypeptide, protein, or peptide.

Amplification of Nucleic Acids

Nucleic acids used as a template for amplification may be isolated fromcells, tissues or other samples according to standard methodologies(Sambrook et al, 2001). In certain embodiments, analysis is performed onwhole cell or tissue homogenates or biological fluid samples withoutsubstantial purification of the template nucleic acid. The nucleic acidmay be genomic DNA or fractionated or whole cell RNA. Where RNA is used,it may be desired to first convert the RNA to a complementary DNA.

The term “primer,” as used herein, is meant to encompass any nucleicacid that is capable of priming the synthesis of a nascent nucleic acidin a template-dependent process. Typically, primers are oligonucleotidesfrom ten to twenty and/or thirty base pairs in length, but longersequences can be employed. Primers may be provided in double-strandedand/or single-stranded form, although the single-stranded form ispreferred.

Pairs of primers designed to selectively hybridize to nucleic acidscorresponding to sequences of genes identified herein are contacted withthe template nucleic acid under conditions that permit selectivehybridization. Depending upon the desired application, high stringencyhybridization conditions may be selected that will only allowhybridization to sequences that are completely complementary to theprimers. In other embodiments, hybridization may occur under reducedstringency to allow for amplification of nucleic acids containing one ormore mismatches with the primer sequences. Once hybridized, thetemplate-primer complex is contacted with one or more enzymes thatfacilitate template-dependent nucleic acid synthesis. Multiple rounds ofamplification, also referred to as “cycles,” are conducted until asufficient amount of amplification product is produced.

The amplification product may be detected or quantified. In certainapplications, the detection may be performed by visual means.Alternatively, the detection may involve indirect identification of theproduct via chemiluminescence, radioactive scintigraphy of incorporatedradiolabel or fluorescent label or even via a system using electricaland/or thermal impulse signals (Bellus, 1994).

A number of template dependent processes are available to amplify theoligonucleotide sequences present in a given template sample. One of thebest known amplification methods is the polymerase chain reaction(referred to as PCR™) which is described in detail in U.S. Pat. Nos.4,683,195, 4,683,202 and 4,800,159, and in Innis et al., 1988, each ofwhich is incorporated herein by reference in their entirety.

Alternative methods for amplification of target nucleic acid sequencesthat may be used in the practice of the present invention are disclosedin U.S. Pat. Nos. 5,843,650, 5,846,709, 5,846,783, 5,849,546, 5,849,497,5,849,547, 5,858,652, 5,866,366, 5,916,776, 5,922,574, 5,928,905,5,928,906, 5,932,451, 5,935,825, 5,939,291 and 5,942,391, GB ApplicationNo. 2 202 328, and in PCT Application No. PCT/US89/01025, each of whichis incorporated herein by reference in its entirety.

Methods of Gene Transfer

Suitable methods for nucleic acid delivery to effect expression ofcompositions of the present invention are believed to include virtuallyany method by which a nucleic acid (e.g., DNA, including viral andnonviral vectors) can be introduced into a cell, a tissue or anorganism, as described herein or as would be known to one of ordinaryskill in the art. Such methods include, but are not limited to, directdelivery of DNA such as by injection (U.S. Pat. Nos. 5,994,624,5,981,274, 5,945,100, 5,780,448, 5,736,524, 5,702,932, 5,656,610,5,589,466 and 5,580,859, each incorporated herein by reference),including microinjection (Harland and Weintraub, 1985; U.S. Pat. No.5,789,215, incorporated herein by reference); by electroporation (U.S.Pat. No. 5,384,253, incorporated herein by reference); by calciumphosphate precipitation (Graham and Van Der Eb, 1973; Chen and Okayama,1987; Rippe et al., 1990); by using DEAE dextran followed bypolyethylene glycol (Gopal, 1985); by direct sonic loading (Fechheimeret al, 1987); by liposome mediated transfection (Nicolau and Sene, 1982;Fraley et al, 1979; Nicolau et al, 1987; Wong et al, 1980; Kaneda et al,1989; Kato et al, 1991); by microprojectile bombardment (PCT ApplicationNos. WO 94/09699 and 95/06128; U.S. Pat. Nos. 5,610,042; 5,322,7835,563,055, 5,550,318, 5,538,877 and 5,538,880, and each incorporatedherein by reference); by agitation with silicon carbide fibers (Kaeppleret al, 1990; U.S. Pat. Nos. 5,302,523 and 5,464,765, each incorporatedherein by reference); by Agrobacterium mediated transformation (U.S.Pat. Nos. 5,591,616 and 5,563,055, each incorporated herein byreference); or by PEG mediated transformation of protoplasts (Omirullehet al, 1993; U.S. Pat. Nos. 4,684,611 and 4,952,500, each incorporatedherein by reference); by desiccation/inhibition mediated DNA uptake(Potrykus et al, 1985). Through the application of techniques such asthese, organelle(s), cell(s), tissue(s) or organism(s) may be stably ortransiently transformed.

The Antibodies of the Invention—and their Production/Isolation

Antibodies directed against the proteins of the invention are useful foraffinity chromatography, immunoassays, and fordistinguishing/identifying Klebsiella proteins as well as for passiveimmunisation and therapy.

Antibodies to the proteins of the invention, both polyclonal andmonoclonal, may be prepared by conventional methods. In general, theprotein is first used to immunize a suitable animal, preferably a mouse,rat, rabbit or goat. Rabbits and goats are preferred for the preparationof polyclonal sera due to the volume of serum obtainable, and theavailability of labeled anti-rabbit and anti-goat antibodies.Immunization is generally performed by mixing or emulsifying the proteinin saline, preferably in an adjuvant such as Freund's complete adjuvant,and injecting the mixture or emulsion parenterally (generallysubcutaneously or intramuscularly). A dose of 50-200 μg/injection istypically sufficient. Immunization is generally boosted 2-6 weeks laterwith one or more injections of the protein in saline, preferably usingFreund's incomplete adjuvant. One may alternatively generate antibodiesby in vitro immunization using methods known in the art, which for thepurposes of this invention is considered equivalent to in vivoimmunization. Polyclonal antiserum is obtained by bleeding the immunizedanimal into a glass or plastic container, incubating the blood at 25 Cfor one hour, followed by incubating at 4 C for 2-18 hours. The serum isrecovered by centrifugation (eg. 1,000 g for 10 minutes). About 20-50 mlper bleed may be obtained from rabbits.

Monoclonal antibodies are prepared using the standard method of Kohler &Milstein [Nature (1975) 256: 495-96], or a modification thereof.Typically, a mouse or rat is immunized as described above. However,rather than bleeding the animal to extract serum, the spleen (andoptionally several large lymph nodes) is removed and dissociated intosingle cells. If desired, the spleen cells may be screened (afterremoval of nonspecifically adherent cells) by applying a cell suspensionto a plate or well coated with the protein antigen. B-cells expressingmembrane-bound immunoglobulin specific for the antigen bind to theplate, and are not rinsed away with the rest of the suspension.Resulting B-cells, or all dissociated spleen cells, are then induced tofuse with myeloma cells to form hybridomas, and are cultured in aselective I aedium (elg. hypexanthine, aminopterin, thymidine medium,“HAT”). The resulting hybridomas are plated by limiting dilution, andare assayed for production of antibodies, which bind specifically to theimmunizing antigen (and which do not bind to unrelated antigens). Theselected MAb-secreting hybridomas are then cultured either in vitro (eg.in tissue culture bottles or hollow fiber reactors), or in vivo (asascites in mice).

If desired, the antibodies (whether polyclonal or monoclonal) may belabeled using conventional techniques. Suitable labels includefluorophores, chromophores, radioactive atoms (particularly 32p and1251), electron-dense reagents, enzymes, and ligands having specificbinding partners. Enzymes are typically detected by their activity. Forexample, horseradish peroxidase is usually detected by its ability toconvert 3,3′, 5,5′-tetramethylbenzidine (TMB) to a blue pigment,quantifiable with a spectrophotometer. “Specific binding partner” refersto a protein capable of binding a ligand molecule with high specificity,as for example in the case of an antigen and a monoclonal antibodyspecific therefor. Other specific binding partners include biotin andavidin or streptavidin, IgG and protein A, and the numerousreceptor-ligand couples known in the art. It should be understood thatthe above description is not meant to categorize the various labels intodistinct classes, as the same label may serve in several differentmodes. For example, 1151 may serve as a radioactive label or as anelectron-dense reagent. HRP may serve as enzyme or as antigen for a MAb.Further, one may combine various labels for desired effect. For example,MAbs and avidin also require labels in the practice of this invention:thus, one might label a MAb with biotin, and detect its presence withavidin labeled with, 1251, or with an anti-biotin MAb labeled with HRP.Other permutations and possibilities will be readily apparent to thoseof ordinary skill in the art, and are considered as equivalents withinthe scope of the instant invention.

According to the invention, the isolated monoclonal antibody or antibodyanalogue is preferably a monoclonal antibody selected from amulti-domain antibody such as a murine antibody, a chimeric antibodysuch as a humanized antibody, a fully human antibody, and single-domainantibody of a llama or a camel, or which is an antibody analogueselected from a fragment of an antibody such as an Fab or an F(ab′)₂, anscFV; cf. also the definition of the term “antibody” presented above.

Compositions of the Invention; Vaccines

Pharmaceutical compositions, in particular vaccines, according to theinvention may either be prophylactic (ie. to prevent infection) ortherapeutic (ie, to treat disease after infection).

Such vaccines comprise immunising antigen(s), immunogen(s),polypeptide(s), protein(s) or nucleic acid(s), usually in combinationwith “pharmaceutically acceptable carriers”, which include any carrierthat does not itself induce the production of antibodies harmful to theindividual receiving the composition.

In some embodiments of the invention, the pharmaceutical compositionssuch as vaccines include merely one single antigen, immunogen,polypeptide, protein, nucleic acid or vector of the invention, but inother embodiments, the pharmaceutical compositions comprise “cocktails”of the antigens or of the immunogens or of the polypeptides or of theprotein or of the nucleic acids or of the vectors of the invention.

In particularly interesting embodiments, the pharmaceutical compositionis an MVA vector mentioned herein, which encodes and can effectexpression of at least 2 nucleic acid fragments of the invention.

Another interesting embodiment of a pharmaceutical composition comprisesRNA as the active principle, i.e. at least one mRNA encoding apolypeptide of the invention.

An embodiment of a pharmaceutical composition of the invention comprisesY or at least Y or at most Y distinct polypeptides of the inventiondescribed above, where each of said Y or at least Y or at most Ydistinct polypeptides comprises an immunogenic amino acid sequencepresent in or derived from any one of SEQ ID NOs: 1-30 and wherein saidY or at least Y or at most Y distinct polypeptides together compriseimmunogenic amino acid sequences present in or derived from Y or atleast Y or at most Y of SEQ ID NOs: 1-30, 93 or 94, wherein Y is aninteger selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, and 32.

Another embodiment of the pharmaceutical composition of the inventioncomprises Z or at least Z or at most Z distinct nucleic acid molecules(such as DNA and RNA) each encoding a polypeptide of the invention,where each of said Z or at least Z or at most Z distinct nucleic acidmolecules encodes an immunogenic amino acid sequence present in orderived from any one of SEQ ID NOs: 1-30, 93, or 94 and wherein said atZ or least Z distinct nucleic acid molecules together encode immunogenicamino acid sequences present in or derived from Z or at least Z or atmost Z of SEQ ID NOs: 1-30, 93, or 94, wherein Z is an integer selectedfrom 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, and 32.

Suitable carriers are typically large, slowly metabolized macromoleculessuch as proteins, polysaccharides, polylactic acids, polyglycolic acids,polymeric amino acids, amino acid copolymers, lipid aggregates (such asoil droplets or liposomes), and inactive virus particles.

Such carriers are well known to those of ordinary skill in the art.Additionally, these carriers may function as immunostimulating agents(“adjuvants”). Furthermore, the antigen or immunogen may be conjugatedto a bacterial toxoid, such as a toxoid from diphtheria, tetanus,cholera, H. pylori, etc. pathogen, cf. the description of immunogeniccarriers supra.

The pharmaceutical compositions of the invention thus typically containan immunological adjuvant, which is commonly an aluminium based adjuvantor one of the other adjuvants described in the following:

Preferred adjuvants to enhance effectiveness of the composition include,but are not limited to: (1) aluminum salts (alum), such as aluminumhydroxide, aluminum phosphate, aluminum sulfate, etc; (2) oil-in-wateremulsion formulations (with or without other specific immunostimulatingagents such as muramyl peptides (see below) or bacterial cell wallcomponents), such as for example (a) MF59 (WO 90/14837; Chapter 10 inVaccine design: the subunit and adjuvant approach, eds. Powell & Newman,Plenum Press 1995), containing 5% Squalene, 0.5% Tween 80, and 0.5% Span85 (optionally containing various amounts of MTP-PE (see below),although not required) formulated into submicron particles using amicrofluidizer such as Model 110Y microfluidizer (Microfluidics, Newton,Mass.), (b) SAF, containing 10% Squalane, 0.4% Tween 80, 5%pluronic-blocked polymer L121, and thr-MDP (see below) eithermicrofluidized into a submicron emulsion or vortexed to generate alarger particle size emulsion, and (c) Ribi adjuvant system (RAS), (RibiImmunochem, Hamilton, Mont.) containing 2% Squalene, 0.2% Tween 80, andone or more bacterial cell wall components from the group consisting ofmonophosphoryl lipid A (MPL), trehalose dimycolate (TDM), and cell wallskeleton (CWS), preferably MPL+CWS (Detox™); (3) saponin adjuvants suchas Stimulon™ (Cambridge Bioscience, Worcester, Mass.) may be used orparticles generated therefrom such as ISCOMs (immunostimulatingcomplexes); (4) Complete Freund's Adjuvant (CFA) and Incomplete Freund'sAdjuvant (IFA); (5) cytokines, such as interleukins (eg. IL-1, IL-2,IL-4, IL-5, IL-6, IL-7, IL-12, etc.), interferons (eg. gammainterferon), macrophage colony stimulating factor (M-CSF), tumornecrosis factor (TNF), etc.; and (6) other substances that act asimmunostimulating agents to enhance the effectiveness of thecomposition. Alum and MF59™ adjuvants are preferred.

As mentioned above, muramyl peptides include, but are not limited to,N-acetyl-muramyl-L-threonyl-D-isoglutamine (thr-MDP),N-acetyl-normuramyl-L-alanyl-D-isoglutamine (nor-MDP),N-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2″-2′-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamine(MTP-PE), etc.

The immunogenic compositions (eg. the immunising antigen or immunogen orpolypeptide or protein or nucleic acid, pharmaceutically acceptablecarrier, and adjuvant) typically will contain diluents, such as water,saline, glycerol, ethanol, etc. Additionally, auxiliary substances, suchas wetting or emulsifying agents, pH buffering substances, and the like,may be present in such vehicles.

Typically, the immunogenic compositions are prepared as injectables,either as liquid solutions or suspensions; solid forms suitable forsolution in, or suspension in, liquid vehicles prior to injection mayalso be prepared. The preparation also may be emulsified or encapsulatedin liposomes for enhanced adjuvant effect, as discussed above underpharmaceutically acceptable carriers.

Immunogenic compositions used as vaccines comprise an immunologicallyeffective amount of the antigenic or immunogenic polypeptides, as wellas any other of the above-mentioned components, as needed. By“immunologically effective amount”, it is meant that the administrationof that amount to an individual, either in a single dose or as part of aseries, is effective for treatment or prevention. This amount variesdepending upon the health and physical condition of the individual to betreated, the taxonomic group of individual to be treated (eg. nonhumaprimate, primate, etc.), the capacity of the individual's immune systemto synthesize antibodies or generally mount an immune response, thedegree of protection desired, the formulation of the vaccine, thetreating doctor's assessment of the medical situation, and otherrelevant factors. It is expected that the amount will fall in arelatively broad range that can be determined through routine trials.However, for the purposes of protein vaccination, the amountadministered per immunization is typically in the range between 0.5 μgand 500 mg (however, often not higher than 5,000 μg), and very often inthe range between 10 and 200 μg.

The immunogenic compositions are conventionally administeredparenterally, eg, by injection, either subcutaneously, intramuscularly,or transdermally/transcutaneously (eg. WO98/20734). Additionalformulations suitable for other modes of administration include oral andpulmonary formulations, suppositories, and transdermal applications. Inthe case of nucleic acid vaccination, also the intravenous orintraarterial routes may be applicable.

Dosage treatment may be a single dose schedule or a multiple doseschedule. The vaccine may be administered in conjunction with otherimmunoregulatory agents.

As an alternative to protein-based vaccines, DNA vaccination (alsotermed nucleic acid vaccination or gene vaccination) may be used [eg.Robinson & Torres (1997) Seminars in Immunol 9: 271-283; Donnelly et al.(1997) Avnu Rev Innnunol 15: 617-648; later herein].

A further aspect of the invention is as mentioned above the recognitionthat combination vaccines can be provided, wherein 2 or more antigensdisclosed herein are combined to enhance the immune response by thevaccinated animal, including to optimize initial immune response andduration of immunity. For the purposes of this aspect of the invention,multiple antigenic fragments derived from the same, longer protein canalso be used, such as the use of a combination of different lengths ofpolypeptide sequence fragments from one protein.

Thus, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 1 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94 or incombination with a variant or fragment disclosed herein of any one ofSEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 2 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 3 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 4 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 5 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 6 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 7 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 8 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 9 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 10 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 11 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,and 16 or in combination with a variant or fragment disclosed herein ofany one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, and 16.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 12 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 13 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 14 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ NOs: 1, 3, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 15 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 3, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 16 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 17 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 18 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 19 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 20 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 21 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 22 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 23 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 24 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 25 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 26 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 27 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 28 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 29 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 30 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 93 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Also, embodiments of the invention relate to a composition (or the useas a vaccine thereof) comprising 2 distinct (i.e. non-identical)proteinaceaous immunogens disclosed herein wherein the first of saidimmunogens is SEQ ID NO: 94 or a variant or fragment thereof disclosedherein in combination with a proteinaceous immunogen selected from anyone of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94or in combination with a variant or fragment disclosed herein of any oneof SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 93, and 94.

Treatment Methods of the Invention

The method of the sixth aspect of the invention generally relates toinduction of immunity and as such also entails method that relate totreatment, prophylaxis and amelioration of disease.

When immunization methods entail that a polypeptide of the invention ora composition comprising such a polypeptide is administered the animal(e.g. the human) typically receives between 0.5 and 5,000 μg of thepolypeptide of the invention per administration.

In preferred embodiments of the sixth aspect, the immunization schemeincludes that the animal (e.g. the human) receives a primingadministration and one or more booster administrations.

Preferred embodiments of the 6^(th) aspect of the invention comprisethat the administration is for the purpose of inducing protectiveimmunity against K. pneumoniae. In this embodiment it is particularlypreferred that the protective immunity is effective in reducing the riskof attracting infection with K. pneumoniae or is effective in treatingor ameliorating infection with K. pneumoniae.

As mentioned herein, the preferred vaccines of the invention inducehumoral immunity, so it is preferred that the administration is for thepurpose of inducing antibodies specific for K. pneumoniae and whereinsaid antibodies or B-lymphocytes producing said antibodies aresubsequently recovered from the animal.

But, as also mentioned the method of the 6^(th) aspect may also beuseful in antibody production, so in other embodiments theadministration is for the purpose of inducing antibodies specific for K.pneumoniae and wherein B-lymphocytes producing said antibodies aresubsequently recovered from the animal and used for preparation ofmonoclonal antibodies.

Pharmaceutical compositions can as mentioned above comprisepolypeptides, antibodies, or nucleic acids of the invention. Thepharmaceutical compositions will comprise a therapeutically effectiveamount thereof.

The term “therapeutically effective amount” or “prophylacticallyeffective amount” as used herein refers to an amount of a therapeuticagent to treat, ameliorate, or prevent a desired disease or condition,or to exhibit a detectable therapeutic or preventative effect. Theeffect can be detected by, for example, chemical markers or antigenlevels. Therapeutic effects also include reduction in physical symptoms,such as decreased body temperature. The precise effective amount for asubject will depend upon the subject's size and health, the nature andextent of the condition, and the therapeutics or combination oftherapeutics selected for administration. Thus, it is not useful tospecify an exact effective amount in advance. Reference is however madeto the ranges for dosages of immunologically effective amounts ofpolypeptides, cf. above.

However, the effective amount for a given situation can be determined byroutine experimentation and is within the judgement of the clinician.

For purposes of the present invention, an effective dose will be fromabout 0.01 mg/kg to 50 mg/kg or 0.05 mg/kg to about 10 mg/kg of the DNAconstructs in the individual to which it is administered.

A pharmaceutical composition can also contain a pharmaceuticallyacceptable carrier. The term “pharmaceutically acceptable carrier”refers to a carrier for administration of a therapeutic agent, such asantibodies or a polypeptide, genes, and other therapeutic agents. Theterm refers to any pharmaceutical carrier that does not itself inducethe production of antibodies harmful to the individual receiving thecomposition, and which may be administered without undue toxicity.Suitable carriers may be large, slowly metabolized macromolecules suchas proteins, polysaccharides, polylactic acids, polyglycolic acids,polymeric amino acids, amino acid copolymers, and inactive virusparticles. Such carriers are well known to those of ordinary skill inthe art.

Pharmaceutically acceptable salts can be used therein, for example,mineral acid salts such as hydrochlorides, hydrobromides, phosphates,sulfates, and the like; and the salts of organic acids such as acetates,propionates, malonates, benzoates, and the like. A thorough discussionof pharmaceutically acceptable excipients is available in Remington'sPharmaceutical Sciences (Mack Pub. Co., N.J. 1991).

Pharmaceutically acceptable carriers in therapeutic compositions maycontain liquids such as water, saline, glycerol and ethanol.Additionally, auxiliary substances, such as wetting or emulsifyingagents, pH buffering substances, and the like, may be present in suchvehicles. Typically, the therapeutic compositions are prepared asinjectables, either as liquid solutions or suspensions; solid formssuitable for solution in, or suspension in, liquid vehicles prior toinjection may also be prepared. Liposomes are included within thedefinition of a pharmaceutically acceptable carrier.

As is apparent from the claims, the invention also relates to relatedembodiments to the treatment and prophylaxis disclosed herein: theinvention also includes embodiments where

-   -   the polypeptide of the invention is for use as a pharmaceutical,        in particular for use as a pharmaceutical in the treatment,        prophylaxis or amelioration of infection with K. pneumoniae;    -   the nucleic acid fragment of the invention or the vector of the        invention is for use as a pharmaceutical, in particular for use        as a pharmaceutical in the treatment, prophylaxis or        amelioration of infection with K. pneumoniae;    -   the transformed cell of the invention is for use as a        pharmaceutical, in particular for use as a pharmaceutical in the        treatment, prophylaxis or amelioration of infection with K.        pneumoniae.    -   the antibody, antibody fragment or antibody analogue of the        invention is for use as a pharmaceutical, in particular for use        as a pharmaceutical in the treatment, prophylaxis or        amelioration of infection with K. pneumoniae.

Sequence Information

The sequence listing included sets forth the sequences of polypeptidesand nucleic acids of the present invention. For easy reference, thesequences are presented in the following:

The polypeptides of the invention have or derive from the followingamino acid sequences:

SEQ ID NO: 1MKKLALLSAVMTLGMSSWAFAADNPPPPPEKGAQHQGKPPVKNGQHEGKQAQYNRKQPQRDGKQPQHDGKQPQHNGKQPPKGSEHSGKPLPPKA SEQ ID NO: 2MKRYATALLFCTLSLTSLAARADIIDDAIGNIQQAINDAYNPGSSRSDDDDRYDDDGRYDDGRYQGSRQQSRDSQRQYDERQRQLDERRRQLDERQRQLDRDRRQLESDQRRLDDSY SEQ ID NO: 3MFRSLILAAVLLAAGPLVANAGEITLLPSVKLQIGDRDNYGNYWDGGSWRDRDYWRRHYEWRDNRWHRHDNGWHKGWYKGRDKAWERGYRAGWNDRDDHRGGWGRGPGGRGHGHGHGHH SEQ ID NO: 4MKEIGLPLLLLTALASPAFAADCQPNGIGGSFCINDDGTTTDTVPNEVNGMDTYSNNGGYTSSLPDRSGADEALEGSSLSTQQGVGSGQSDSALAGRDWHSPANLNDGAATSSMSLLDKP SEQ ID NO: 5MNMKKLTTLLLTATLGLASGAALAADTGAQSNNGQANSSADAGQVAPDARENVAPNNVDNSQINSGSGGTTGSTMTQDNMSSNEVHKNSMCKDGRCPDTGKKLDNGGNTTQDNSKTDGTTQ SEQ ID NO: 6MKHRIALLLVLTSLSASALAASPCQEKEQDIQREISYAEKHHNQSRIDGLNTALRQVRENCSDSKLKADHQQKIAKQREEIAERQRDLQEARKKGDADKINKRQHKLNEAQQELKTLESRDY SEQ ID NO: 7MRLITRHVREDIMKKAMIALSAILVAAPVFAATTHATDDTVAAANANANTAKEKLHQAQHEGEEQQLKAKHAAEGKQDSVGSQVSEGAQKTWNKTKEGTEKGWDKTKEVSEKGWNATKSGAEKGWDKTKTGAEELK NKVTESEQ ID NO: 8MKKMISLAVILSCVLSVPAFADGPNDGHRPEQPTVWQNGPDHDGHAPQGGPDAHHQGDHDQRGPDRDGHDKRDLARHEQDHFAWRGNDFRKGHPAPAPFRGDEYRVRDWSDRGLPPPPEGHHWSYIDGNYVLIAAATGIITSILVSGALGH SEQ ID NO: 9MKKPTSATRGKSGRKSREELNQEARDRKRQKKHRGHAAGSRANGGDAASAGKKQRQAQDPRVGSKKPIPLGVSESSVPAPKQHKPKSEKPMLSPQAELELLENDERLDALLERLEEGGTLNAEEQSWVDAKLDRIDELMQQLGLSYDDEDEEEEERQEDMMRLLKGGN SEQ ID NO: 10MASKFQNRLVGTIVLVALGVIILPGLLDGQKKHYQDEFAAIPLVPKPGDRDEPDMLPAATQALPSQPPEGAAEEVRAGDAAAPSLDPSRIPVNSNSFDDVQEPVVAAKPQPKPQPKPQPQQQASTPTPPPAKPQQQQPPQQQAALPAPTGKAYVVQLGALKNADKVNEIVGKLRASGFKVYTSPSTPVQGKITRILVGPDASKDKLKGQLGDLQQISGLSGVVMGFTPN SEQ ID NO: 11MAQRDYVRRSQPASSRRKKSTTRSSRNKQSSLPAISPAMVAIAAAVLVAFIGGLYFITHHKKEEAEAMQNRQAAGNGLPPKPEERWRYIKELESRQPGVRAPTEPTAGGEVMKPEQLTDEQRQLLAQMQADMRQQPTQLTEVPWNEQTPAQRQQTLQRQRLAQQQQQAQQQQWAQTQAQTVQQQPPRVQQPKPVQQQQPKQTASNQQPYQDLLQTPAHTNTTQPRTQAAAPVTRVEEAPKTTAEKKDDRSWMIQCGSFKGAEQAETVRAQLAFEGFASHITTNNGWNRVVIGPLKGKESANEMITRLKMAGHANCIRLAARG SEQ ID NO: 12MSAGSTKFTVSRIAALSLVSLWLAGCTNTNNPPAPVSSAGGAASSSTNSGMLITPPPSGVKSAPQAQPIQPMQTQTIQPAPVAQEPVQTVNGRIVYNRKYGDIPKGSYTGGSTYTVKRGDTLFYIAWVTGNDFRDLAQRNNIPAPYALNVGQVLQVGNASGQPITGENAVSQASARASGGATTSTTSAQKSTAVVASQPTITYSESSGEQSATKMLPNNKPATTTTTVVAPVTAPTTVSTTQPTASSTSTSSPISAWRWPTDGKVIENFSGAEGGNKGIDIAGSKGQAIVATADGRVVYAGNALRGYGNLIIIKHNDDYLSAYAHNDTMLVREQQEVKAGQKIATMGSTGTSSTRLHFEIRYKGKSVNPLQYLPQR SEQ ID NO: 13MRKQWLGICIAAGLLAACSSDDVQQKTVSTPQPAVCNGPTVEISGADPQYETPNATANQDYERDGKSYKIVQDPANFTQAGFAAIYDAEPNSNLTASGEAFDPTQLTAAHPTLPIPSYARITNLANGRMIVVRINDRGPYGNDRVISLSRASADRLNTSNNTKVRIDPIIVAPDGSLSGPGMACTTVAKQTYALPARPNLDGGDAAGMSQPAPTDVRPISNSTLTPADSVGAPVNSGGFLGAPTPLNNGVLESSEPAAAAATAPAAGATPTAPVTAPGSIQGNVVPAAATAAAAGAVAASSSATSSASGNFVVQVGAVSDQTRAQQYQQRLSQQFSVPGRVMQNGAVWRIQLGPFADKAQASAVQQRLQSEAQLQSFITRAN SEQ ID NO: 14MDDFKPEDDMKADRNDRRAGRSRQSSERDADPQINFDDVDLDADEGRPTRAGKARREREEEEFEEELDAQDEEMLEEQPVERRPRKRKKAPAKPASRQYIMMGVGILVLLLLIVGIGSALKSPSSSSQQTASGEKSINLSDDQSASMPAAGQDQTAAANSTSQQDVTVPPIAANPTQGQAAVAPQGQQRIEVQGDLNNALTQQQGQLDGAVANSTLPTEPATVAPIRNGANGTAAPRQATERQTAATPRPAERKHTVIEAKPQSKPQAVAKTPVESKPVQPKHVESTATTAPAKTSVSESKPVATAQSKPTTTTAAPAATAAAAAPAAKTGKTAGDVSSMKTAPSGHYTLQLSSSSNYDNLNNWAKKEKLDKYVVYETSRNGQPWYVLVSGIYASKDEAKRAVTSLPADVQAKNPWAKPLHQVQADLK SEQ ID NO: 15MSKATEQNDKLKRAIIISVALHIILIALLIWSSFDEHLDASAGGGGGSSIDAVMVDPGAVVNNYNRQQQQQASARRAAEQREKQAQQQAEELREKQAAEQERLKQLEQERLQAQEAAKEAKEQQKQAEEAAAKAAAAAKAKADAQAKEAQEAAAKAAAEAKAKADAQAKAAEQAAAKAAADAKKQAEAAAAKAAAEAKKQAEAEAAKAAAEAQKKAEAAAAKKAQQEAEKKAQQEAAKQAAAEKAAAEKAAEKAAAQKAAAEKAAAEKAAAAEKAAAAKAAAAEKAAADKAAKAAAAKAAAAKKAAAAKEADGVDNLLGDLSSGKNAPKTGGGAKGNNASAAGSGNTKNSASGADINNYAGQIKSAIESKFYDASSYAGKTCTLRIKLAPDGLLLNIQSEGGDPALCQAALAAARQAKFPKPPSQAVYEVFKNAPLDFKPQ SEQ ID NO: 16MFFLSIFYMEMTKVKLSALFIALIPLLGSPVIHAETTAAPVLENRAAQGDITTPGGARRLTGDQTEALRASLINKPAKNVILLIGDGMGDSEITAARNYAEGAGGFFKGIDALPLTGQYTHYSLDKKTGKPDYVTDSAASATAWTTGVKTYNGALGVDIHENAHQTILELAKAAGLATGNVSTAELQDATPAALVAHVTSRKCYGPTVTSEKCPSNALEKGGKGSITEQLLNARPDVTLGGGAKTFTETATAGEWQGKTLREQAQARGYQIVTDAASLAAATEASQDKPLLGLFADGNMPVRWEGPKASYHGNIDKPPVTCTPNPKRDASVPTLAQMTEKAIDLLSRNEKGFFLQVEGASIDKQDHAANPCGQIGETVDLDEAVQKALEFARKDGNTLVIVTADHAHASQIIPADSKAPGLTQALNTHDGAVMVMSYGNSEEESMEHTGTQLRIAAYGPHAANVVGLTDQTDLFTTMKAALSLKSEQ ID NO: 17MSLPFKPHIIALLCSAGLLAAAGTLYVQSRTPATIAEPPAQQAPAPAASTTQPVAATYTQAQIDQWVAPIALYPDSLLSQVLMASTYPDNVLQAVQWSQDNPAMKGDAAVQAVASQPWDPSVKSLVAFPALLAMMGENPPWVENLGNAFLAQPHDVMDSVQRLRAIAQQTGTLKSTPQQKVIVTPAAPVSASSSTAATATAHTAAPAPTQVIKIEPTNPQVVYVPSYNPSTVYGTWPNSAYPPVYLPPPPGEQFTDSFVKGFGYSLGVATTWALFSSIDWDDDDHHHHDDDYHHGDYSHNGDNININVNNFNHITGENLPGNHVNWQHNPAYRGHTPYPDNTVAQRFHQTNVSGGLSATQHAPVDREAQRQAAMTQLQHNVPTATAGNLAANNASRDAQRQAASAQLKQATQRSNYRGYDSTPTQQQRREAAKTQLKNPTPQQQQRREAARSHEQNRTPQQQQRRQQFQSATPAQRQQTLSHLRANALSGNESRAPSWQAQQERGLQSRQFSGVNRELRDGTRERLSEHHELRRR SEQ ID NO: 18MFKFKASYVALAAVLTSSVVYADPTSYTHSSGATVIDIEKPNAAGVSHNLYRDFNVGANGTILNNSGDDVSHSTFGNIARNNNLTAGSASVILNEVTSKNASSLKGFIEVNGQKADVVIANPNGITCSGCSFVNTNKAILTTGKVNMTDDGAIGSYTVTGGTLTIGENGMNAANGYAVLLADAININGKVQANNALVSAGNFTMDNSSGSVTSAGKKATLIQMTVNPQYSIDVSSLGGIEANSISMVGNNIGFGVRNKGSIVANSSLQLTSNGNLLNKGTIKSNGLLSQVATASGITNDGSIAGAYYLMLSSGDYIVNTGSLSGGQLIATANGNITNGDSGTMTGTSGLSLTSGGKIRNEEKASLLSNNQIAATAIGDFLNEGKISAKHTSLTFVGDSFKNTGNINSTGQTTIQSLKQDGSANTGEIYNLGNITGENINLQTNGTLAQSSSGRIEATNAITAHSYWLNQNGYMNAADITTDHGVVNNYGNITAKNISITTYSDITNEGQISSTGDLTLNTKNKGAIYNYSTLSAGGNMTLTATKVVNGGKSCGILGLAKCGVGTLTADKLVLNSSQKYVSDMGGKQYFKSTEVNTVK SEQ ID NO: 19MMDNLRTAANSVVLKIIFGIIIVSFILTGVSGYLIGGGKNYAAKVNGQEIGRGQFENAVASERNRMQQQLGDQFSELAANENYMKTMRQQVLNRLIDESLLDQYARELGLSISDEQVKQAIFQTQAFQTNGKFDNQRFSGIVAQMGMTTDQYAQALRNQLTTQQLINAIAGTDFMLPGESDQLAALVSQQRVVREATINVNALAAKQTASDEEINAFWQQNQARFMAPEQFRVSYIKMDAASMQESASDEEIQSWYDQHKDQFTQPQRNRYSVIQTKTEADAKAVLAELQKGADFATLAKEKSTDIISARNGGDMGWMEDASTVPELKDAGLKEKGQLSGVIKSSVGFLVARLDDVQPAQVKPLADVRNDIAAKVKQEKALDAYYALQQKVSDAASNDNESLASAAQVAGLKVVETGWFGRDNLPEELNFKPVADAIFNGGLVGENGAPGSNSDIITVDGDRAFVLRISEHKAEAVKPLAEVKAQVSDIVKHNKAEQQAKLEADKLLAALKDGKGDEAMKAAGLSFGAPQTLSRTGQDPLSQLAFTLPLPQQGKPVYGVGSNMQGDVVLVALDEVKAGSMPEEQKKAMVQGITQNNAQIAFEALMSNLRKAAKIKLGDSIDQ QQSEQ ID NO: 20MFRLNPFIRAGLSASVVSLAFPALADVNEETLVVTASATEQNVKDAPASISVITQQDLQRKPVQNLKDVLRDVPGVQLTNEGDNRKGVSIRGLSSSYTLILVDGKRVNSRNAVFRHNDFDLNWIPVDAIERIEVVRGPMSSLYGSDALGGVVNIITKKIGQKWTGTLSADTTIQEHRDRGDTWNGQFFTSGPLIDGVLGMKAYGSLAKRAKDDPQSSSNATGETPRIEGFTSRDGNVEFAWTPNENHDFTAGYGFDRQDRDSDSLDRNRLERENYSLSHNGRWDIGNSELKFYGEKVDNKNPGQSGTITSESNAIDGKYVLPLGMINQLVTFGGEWRHDKLKDPVNLSSGGQSTSASQYALFIEDEWRIIEPLALTTGIRMDDHQTYGDHWSPRAYLVYNATDTVTVKGGWATAFKAPSLLQLNPDWTTNSCRGSCSIVGNPDLKPETSESFELGLYYRGEEGWLENVEGSITTFQNNVDDMIDVLRTSSASEAPGYPNFVGWKTVNGKRVPIFRYFNVNKARIKGVETEVKIPFGDEWKLTVNYTYNDGRDLSNGGDKPLQTLPFHTANGTLDWKPLDDWSFYVTANYTGQQRAVSATGKTPGGYTLFDVGAAWQVTKNVKLRSGVQNVGDKDLSRDDYSYTEEGRRYFMAVDYRF SEQ ID NO: 21MNRAATLTLNAPLLMLVAALALSTPFTAGAAPAFLDYAQQQTQQSQAQEKNDAASAKQTQESRQSADNKKTGTSTSQLQKRITSQQAAIAQKDKLIQQLKKQLAATPQTDTAGANEQAALNKRINELQVALSAATAEKEALIKKAGVVQNNNLQQSQAAARQQIQQLTTQIQQAEAENKRLSASFTTLNKDKHALMTQLAATEKEKQAALEQVKALNADKQPLTTRLAAAEKEKQAVLEQVKALNADKQSLTIRLAAAEKAQQAAVDQAKALNADKQPLATRLAAAEKEKQAVLEQVKALSADKQSLTIRLAAAEKAQQAALDQAKALNADKQPLATRLAAAEKEKQAVLEQVKALNADKQSLTIRLAAAEKTQQAALDQVKALNADKQSLSTRLAAADKAPHGPANDAAAPKNEPPEMAAIVAAYRLQADKDNAQLRMKEDEIELLRTQLSVQSKTRSGESAAAKLSASGEQQAYAIGASMGSEALNVLTTRRTQGVTVDAGLVLQGIEDAFRGQLRLGEQERNKALFDVSQQVFQNLNKIEQKNISAGKKYQQAFARKKDVVFKEGVYSRVDYLGKGKISGNDLVTVVIKEMLTDGTVINDMEAKDQALTQKLDAYPPVFREPLKRLQNHGSVTLVVPPEKAYGSKGLPPKIPPGATMVYSVRIVDSQPEPAK SEQ ID NO: 22MKILSVRHAALPALLLPLIAAAQAADEQTMVVTAAPTTVSELDTPAAVSVVNGDEMRQAAPRVNLSESLGAVPGLQVQNRQNYAQDLQLSIRGFGSRSTYGVRGLRIYVDGIPATMPDGQGQTSNIDIGSVDTIEVLRGPFSALYGNSSGGVINVTSQTGTQPPTVEASSYYGSFGTWHYGMKATGAVGDGSHAGDVDYTVSTNRFTTHGYRDHSGARKNLANARLGVRINDVSKLTLLLNSVDIKANDAGGLTADEWRDNPRQSPRGDQYNTRKNTRQTQAGLRYERQLSAQDDLSVMMYAGERETTQFQSIPRAPQLKPSHAGGVIDLTRHYQGIDTRLTHRGELLVPVTLTAGLDYENMSERRKGYENFVMVNGAPQYGEQGALRRNERNLMWNVDPYLQTQWQLTDKLSLDAGVRYSSVWFDSNDYYITPGNGDDSGDASYHKWLPAGSLKYALTDAWNVYLSAGRGFETPTINELSYRSDNQSGLNFGLKPSTNDTVEIGSKTRIGNGLFTAALFQTNTDNEIVVDSSSGGRTSYKNAGKTRRQGMELGLDQQFGESWRLKAAWTWLDATYRTNVCDDASCNGNRIPGIARNMGYASFGYQPEQGWYAGSDIRYMSDIMANDENTAKAPSWTVVGLTTGYKWSYGRMDMDLFGRIDNLFDREYVGSVIVNESNGRYYEPAPGRNYGIGLNLAWRFE SEQ ID NO: 23MKYTSHFPLGIVIPLLACSVPLQAAENMTEQSTPDESAATAENHEETMVITAARQNLQAPGVSTITAEEIRKHPPARDVSELIRTQPGVNLTGNSTSGQRGNNRQIDIRGMGPENTLVLVDGKPVTSRNSVRYGWRGDRDSRGDTSWVPAEMIDHIDVIRGPAAARYGNGAMGGVVNIVTKPTTREWHGSWNTYMNAPQHRKEGATKRTNFSLNGPLSDSVSFNLWGNLSKTQADAQDINAGHEAERTGSYAGSYPAGREGVVNKDIHSKLRWEFAPMQALEFEAGYSRQGNLYAGDTQNTNTSTLVKSMYGKETNRLYRQTYGVTWTGGWDNGVTSNSYAQYEHTRNSRMDEGLAGGTEGIFSSSEFSDIDLADVLLHSEVNIPFTLGVDQNLTLGAEWNQQRMKDGVSTTQALSYGTIDGVSATGRSPYSSAEIFSLFTEDNMALTDSTMLTPALRFDHHSIVGNNWSPSLNLSQELTDDWTLKLGIARAYKAPNLYQLNPNYILYSNGQGCYASSSACYLMGNSDLKAETSVNKEIGLEYKHDGYQAGITWFRNDYHNKIESGYAAVGTASNGTTNIYQWENVPKALVEGLEGTLNLPVGEAVNWSNNLTWMLQSKNKTTGDRLSVIPQFTLNSTLSWQVREDLSLQSTFTWYGRQKPKRFNYKGEAVSGSELNEVSPYSIVGLSATWDVNKNLSFTSGIDNLFDIRHYRAGNAQTTGNATTGAYLYGAGAETYNESGRTFFMSVNTHFSEQ ID NO: 24MEKNASLPFGSFNSLALFTGLCLGASPAAGIAAENSVKNSEETLVVEAAPPSLYSPGASADPKFNKPLVDTTRTITVIPEQVIKDQGVTNLTDALKNVPGVGAFYAGENGSSTTGDAIFMRGVDTSNSIYVDGIRDIGSVTRDTFNTQQVEVIKGPAGTDYGRSAPSGSINMISKQPRLDSGIDGSASIGSAWSRRGTLDLNQAFSDNAAFRLNLMGEKTHDAGRDRIENERYGIAPSLAFGLDTPTRLYLNYLHVRQNNTPDGGIPTVGLPGYSAPSPKYAALNSAGKVDTSNFYGTDSDYDKSTTDSGTLRFEHDLTENTTVRNTTRWSRVKQEYLLTAVMGGANNITAPDINDVNTWSWSRLVNTKDVSNRILTNQTNITSTFNTGSIGHDVSAGVEFTRENQTNYGVNARTAPAVNLYHPVSNLSIGGLDRNGANANGQTDTFGIYAFDTLTLTERIEINGGLRLDNYHTKYDSATACGGSGRGAIACPPGQSTGSPVTTVDTAKSGNLVNWKAGALYRLTEQGNVYVNYAISQQPPGGSSFALAASGSGNSANRTDFKPQKAKSSELGTKWQIFDNRLLLSAALFRTDIENEVAANDDGTWSQYGKKRVEGYELSATGNLTPDWTIIAGYTQQHATVTEGQNVAQDGSSALAYTPKHAFTLWTQYQATSDLSVGGGVRYVGSLRRGSDGAVGTPDHTEGYWVADAKLGYRVNSNLDLQLNMYNLFDTDYVASINKSGYRYHPGEPRTFMLTANVHFSEQ ID NO: 25MATMYKSTPSAAWCKKRLLVTSLFAAIYQTSAIAADTSAVSGEAVDDTSEQMTVTAPAPVQKAGSEHSISARELENKGANDFGSIMRYEPLISATGASGGSGNGKSGFDRGGYTGYNIRGMESNRVGIDVDGIAQPNATGRGYVGRAGLNTFGIGRDYIDPYMYGSVDIQSGATSTETANSAIGGNVSFRPKSADDYLRPGKTSAFGYRSGYDSADRSWHNGVTVAGGDEFLRGILVYSRRDGQETENNSGTVDAYPANWHSDAFLASGIWQPNDEHKLTSTFDYYHKTNHTHYDTWDSSGNSTIGTANQTSQTRRWGLSLKDDWTPMNDYLDSVSTKIYYQHTEAHDWTYMPDSVTRKMQTVNSNYDTDTWGLQTALAKTLGRHDLSAGFNASTSKTQRPFSQSPIPSVYSEIMQPEADSRSYTLGGFVQDKINFDLDSHNFAVIPGVRVVHQSTKPENLSDLAANSSVLSESSVANLYGKNSDTQVLPSLTFQYDLTPRLMTYLQYQRGAQFPNASQLYGSWNLGSSYAGSQQYALIGNTDLKTETSDNLEWGLKGEVTEGITLRTALFYNSYKNFIAYTRYTRANNPGQFTNVPSNIYTIYQAENRDKAYIYGGEISTKFNFGTWFEQVDGLSATLALGYSEGKSKSSYSGDKYVDLDSVAPMKAIVGVAWDDPAKRYGTALTATFVKGKQATATNRESYSNSGSAITDASSDYMRVPGYGMLDWTAYWQVAKNVRLNGGVYNLTDRKYWDYLSSRNIETGTNQDANDKALAVMPGRTWQLGVNVDF SEQ ID NO: 26MAMKKLLIASLLFSSATVYGAEGFVVKDIHFEGLQRVAVGAALLSMPVRPGDTVTDDDISNTIRALFATGNFEDVRVLRDGDTLLVQVKERPTIASITFSGNKSVKDDMLKQNLEASGVRVGESLDRTTIADIEKGLEDFYYSVGKYSASVKAVVTPLPRNRVDLKLVFQEGVSAKIQQINIVGNHAFSTDELISHFQLRDEVPWWNVVGDRKYQKQKLAGDLETLRSYYLDRGYARFNIDSTQVSLTPDKKGIYITVNITEGDQYKFSGVQVTGNLAGHSAEIEALTKVEPGELYNGAKVTKMENDIKKLLGRYGYAYPRVQSQPEINDSDKTVKLHVNVDAGNRYYVRKIRFEGNDTSKDAVLRREMRQMEGAWLGSDLVDQGKDRLNRLGFFETVDTDTQRVPGSPDQVDVVYKVKERNTGSFNFGIGYGTESGVSFQAGVQQDNWLGTGYAVGINGTKNDYQTYTELSVTNPYFTVDGVSLGGRVFYNDFDANDADLSDYTNKSYGTDITLGFPVNEYNTLRAGVGYVHNSLSNMQPQVAMWRYLNSMGQYPDNTNDRNSFSANDFTFNYGWTYNKLDRGFFPTEGSRVNLNGKVTIPGSDNEYYKATLDTATYVPIDNDHQWVVLGRTRFGYGDGIGGKEMPFYENFYAGGSSTVRGFQSNTIGPKAVYFPASSRHDDDDSYDNECKSTESAPCKSDDAVGGNAMAVASLELITPTPFISDKYANSVRTSVFWDMGTVWDTHWDSSAYAGYPDYSDPSNIRMSAGIAVQWMSPLGPLVFSYAQPFKKYDGDKAEQFQFNIGKTW SEQ ID NO: 27MTDVTIKALASEIQTSVDRLIQQFADAGIRKSADDSVTSQEKQTLLTHLNREHGSAPDKLTLQRKTRSTLNIPGTGGKSKSVQIEVRKKRTFVKRDPQEAERLAAEEQAQREAEEQARREAEEAAKREAQLKAEREAAEQAKREVADKAKREAAEKDKVSNQHTDEMTKTAQAEKIRRENEAAELKRKSEEEARRKLEEEARRVAEEARRMAEENEKNWSETSDSPEDSSDYHVTTSQHARQAEDDNDREVEGGRGRSRSSKAARPAKKGNKHAESKADREEARAAVRGGKGGKHRKGSALQQGFQKPAQAVNRDVVIGETITVGELANKMAVKGSQVIKAMMKLGAMATINQVIDQETAQLVAEEMGHKVILRRENELEEAVMSDRDTGAAAEPRAPVVTIMGHVDHGKTSLLDYIRSTKVASGEAGGITQHIGAYHVETDNGMITFLDTPGHAAFTSMRARGAQATDIVVLVVAADDGVMPQTIEAIQHAKAAQVPVVVAVNKIDKPEADPDRVKNELSQYGILPEEWGGESQFVHVSAKAGTGIDDLLDAILLQAEVLELKAVRNGMASGAVIESFLDKGRGPVATVLVREGTLHKGDIVLCGFEYGRVRAMRDELGREVLEAGPSIPVEILGLSGVPAAGDEVTVVRDEKKAREVALYRQGKFREVKLARQQKSKLENMFANMTEGEVHEVNIVLKADVQGSVEAISDSLLKLSTDEVKVKIIGSGVGGITETDATLAAASNAILVGFNVRADASARKVIEAESLDLRYYSVIYNLIDEVKAAMSGMLSPELKQQIIGLAEVRDVFKSPKFGAIAGCMVTEGTIKRHNPIRVLRDNVVIYEGELESLRRFKDDVNEVRNGMECGIGVKNYNDVRVGDMIEVFEIIEIQRSID SEQ ID NO: 28MKRMLINATQQEELRVALVDGQRLYDLDIESPGHEQKKANIYKGKITRIEPSLEAAFVDYGAERHGFLPLKEIAREYFPANYIVAHGRPNIKDVLREGQEVIVQIDKEERGNKGAALTTFISLAGSYLVLMPNNPRAGGISRRIEGDDRTELKEALASLELPDGMGLIVRTAGVGKSAEALQWDLSFRLKHWEAIQKAAESRPAPFLIHQESNVIVRAFRDYLRQDIGEILIDNPKVLELARQHIAALGRPDFSSKIKLYTGEIPLFSHYQIESQIESAFQREVRLPSGGSIVIDSTEALTAIDINSARATRGGDIEETAFNTNLEAADEIARQLRLRDLGGLIVIDFIDMTPVRHQRAVENRLREAVRQDRARIQISHISRFGLLEMSRQRLSPSLGESSHHVCPRCSGTGTVRDNESLSLSILRLIEEEALKENTKEVHAIVPVPIASYLLNEKRAAVSAIESRQGDVRVIIVPNDEMQTPHYSVLRVRKGEETSTLSYLLPKLHEEEMALPGDDEPAERKRPEQPALAAFVMPDAPPAPMLEEPAAAPVAAAAPVAAAAPAQPGLLSRFFSALKNIFSGAEEAKPAEVQVEKKAEEKPERQQERRKPRANNRRDRNDRRDNRDNRDNRDNRDNRDTRADNAEGREPRESREENRRNRREKPSQNVEARDVRQTSGDDAEKAKSRDEQQPRRERTRRRSDDKRQAQQEAKAQTREEPVVQETEQEERVQTLPRRKPRQLAQKVRVESAVVEPVAEIVPEAVVAEVIAPHSEPVKAELPAGVESVADQDENGESREANGMPRRSRRSPRHLRVSGQRRRRYRDERYPTQSPMPLTVACASPEMASGKVWIRYPVVRPQDQQPEEVQVQDASVAKTVEAVAAPVAVVETVTAAPVTVEPATMEPVTAEPVVVEPVAAAEPLVVDAAEVVAPAAVEPAPQEPVTEAPAVEAPQAIAPVTLDAEPVVVEPEAVETTPVVAAPVETIAPVAETVEQAPVTEAAPAEPVKAEPPVSKPVVVAGHRHATAPMTRAPAPDYVPEAPRHSTWVRPPFAFEGKGAAGGHSATHKATAEPTRPQPVE SEQ ID NO: 29MRKLSLSLLTLSLGVALLPLAQAATTPAQEHLLEQVRLGEASNREDLVRQSLYRLELIDPNNPELIAARMRYLLRQGDAAGAQKELERLTKQAPDSPELKASRNEMKSNTGEGRQALQQARLLGVAGKVDEAIAAYEKLYGGVPDDVDVAIEYWTLVARLPARHSEGVSQLKKLNASAPGNVSLLTSLAKQMFADNKPQEGFAYLAEMARSASGRGIAADMWFSEVKSMPVSKASVQALQQFLLQFPTGSVAANARVLLDQQQAQLQDPTFRARSEGLAAVKSGNTTQAVADLQKAVQADSRDSDAVGALGQAYSQRGDRARAVAQLSKAIAMDPDSPNRGKWDSLLQTNRYWLLIKQGDNALKAGQLSQAQNYYAQAQRVDRTDSYAVLGLGDVAAARKEAAAAERYYQQALRLDRGNNLAVRGLANLYRAESPEKASAWIAGLPPAQRRSIDDIERSLTNDRLEKQAQALESQGNWAQAAEVQRRRLALDPDSVWITYRLARDLVSAGERQEADALMRTMVNRQPQDAERVYASGLYLSGNDQDDLALAQIAALPRSAWTDNIRELEARLQSDRVLRQANQLRDSGNEAQAIALIRQQPASVRYDLTLADWAQQRGDSQTAIANYQRVLRQEADNGDARLGLAEVYLAEGDKPAARAQVMQLKGAETESMNMQRRVALARAGLGDTADAQRIFNQIVPQAKAQPPSMESALVLRDAARFATQSGAPQQALTHYREAMVASGITPAQPQDNDTFTRLTRNDSHDDWLKRGIRSDAADLYRQQDLNVTLEHDFWGSSGTGGYSDLKAHTTMLQMDAPLADGRMFFRTDLVNMDAGSFSTHSDGSYSPSWGTCGEIACTSGSKNQTDSGASVAVGWKNDTWSGDIGTTPMGFNVVDVVGGLSYSSDVGPVGYTVNVHRRPISSSLLSFGGQKDSSSHTGATWGGVRADGGGLSLSYDRGEAHGIWSSLGADSLTGKNVADNWRVRWMTGYYYKVINENNRRVTVGLNNMIWHYDKDLSGYTLGQGGYYSPQEYLSFAVPVTWRQRTENWSWELGGSVSWSHSRTQTQARYPLLNLIPSDYRQRASELTEEGSSSHGFGYTARALVERRVTSNWFVGAAVDIQQAKDYTPSHALLYVRYSAAGWQGDLDMPPQPLVPYADWSEQ ID NO: 30MSQEYTEDKEVKLTKLSSGRRLLEAMLILCSLFAIWLMAALLSFNPSDPSWSQTAWHEPIHNLGGAPGAWLADTLFFIFGVMAYTIPVIIIGGCWFAWRHQENDEYIDYFAVSLRLIGALALILTSCGLAAINADDIWYFASGGVIGSLLSTTLQPLLHSSGGTIALLCIWAAGLTLFTGWSWVSIAEKLGGGILSVLTFASNRTRRDDTWVDEGEYEDDEEEYDDEEAARPQESRRARILRSALARRKRLAEKFTNPMGRKTDAALFSGKRMDDGEEVVQYSASGAPVAADDVLFSGASAARPAEDDVLFSGASAVRPGDFDPYDPLLNGHSIAEPVSAAAAATAAPQAWAESPVGHHGAAPAYQPEASYPPQQAYQPEPAPFQQAYQPEPAPFQQAAYQPPAGQTAPQAYQPEPAPYQQPVYDPRAGQPAPQAYQPEPAPYQQPAYDPYAGQPAPQAYQPEPAPYQQPAYDPHAGQPAPQAYQPEPAPYQQPAYDPYAGQPAPQAYQPEPAPYQQPTYDPYAGQPAPQTYQQPAYDPNAGQPAPQPYQPEPAAYQPQSAPVPPPEPEPEVVQEEVKRPPLYYFEEVEEKRARERELLASWYQPIPEPESPIATKPLTPPTTASKPPVETTVVSAVAAGVHQATAASGGAAAATSSTAASAAATPLFSPASSGPRVQVKEGIGPKLPRPNRVRVPTRRELASYGIKLPSQREAEQRARQAERDPHYDDELLSDEEADAMEQDELARQFAATQQQRYGHRWEDDNATDDDEADAAAEAELARQFAATQQQRYATEQPPGANPFSPADYEFSPMKTLVNDGPSEPLFTPTPEVQPQQPAQRYQQPAAAPQQGYQPAQHQPIHHQPVPPQPQSYPTASQPVQPQQPVAPQGHQPAAPAPQESLIHPLLMRNGDSRPLQKPTTPLPSLDLLTPPPSEVEPVDTFALEQMARLVEARLADFRIKADVVNYSPGPVITRFELNLAPGVKAARISNLSRDLARSLSTVAVRVVEVIPGKPYVGLELPNKKRQTVYLREVLDNAKFRDNPSPLTVVLGKDIAGDPVVADLAKMPHLLVAGTTGSGKSVGVNAMILSMLYKAQPEDVRFIMIDPKMLELSVYEGIPHLLTEVVTDMKDAAIVALRWSVNEMERRYKLMSALGVRNLAGYNEKIAEAARMGRPIPDPYWKPGDSMDAVHPVLEKLPYIVVLVDEFADLMMTVGKKVEELIARLAQKARAAGIHLVLATQRPSVDVITGLIKANIPTRIAFTVSSKIDSRTILDQGGAESLLGMGDMLYSGPNSTMVRVHGAFVRDQEVHAVVQDWKARGRPQYVDGITSDSESEGGGGGFDGGEELDPLFDQAVNFVTEKRKASISGVQRQFRIGYNRAARIIEQMEAQGIVSEQGHNGNREVLAPPPFThe nucleic acid fragments of the present invention have or derive fromthe following sequences: SEQ ID NO: 31ATGAAGAAGTTAGCTTTACTCTCCGCCGTAATGACGCTTGGAATGTCGTCATGGGCTTTTGCTGCCGACAACCCGCCGCCGCCGCCGGAAAAAGGCGCGCAGCATCAGGGTAAACCGCCGGTGAAAAACGGCCAACACGAAGGTAAGCAAGCGCAATACAACAGAAAACAGCCACAACGAGACGGCAAACAGCCGCAGCACGACGGTAAACAGCCGCAGCACAACGGCAAGCAGCCGCCAAAAGGGAGCGAGCACAGCGGGAAACCGCTGCCGCCGAAAGCGTAA SEQ ID NO: 32ATGAAACGTTACGCAACCGCACTGCTCTTTTGCACTCTGTCGCTGACCAGCCTGGCCGCTCGCGCCGATATTATCGATGACGCGATCGGCAATATTCAGCAAGCCATTAACGACGCCTATAACCCCGGCAGCAGTCGCTCCGATGACGACGACAGATACGATGACGATGGCCGGTATGATGACGGGCGCTATCAGGGGAGCCGTCAGCAGAGCCGTGACAGTCAGCGCCAGTATGACGAGCGGCAACGCCAGCTGGACGAGCGCCGCCGCCAGCTGGATGAACGCCAGCGTCAGCTCGACCGCGATCGTCGTCAGTTAGAAAGCGACCAGCGTCGTCTGGATGATAGCTACTGA SEQ ID NO: 33ATGTTCAGGTCACTGATTCTGGCAGCAGTACTGCTGGCCGCAGGGCCACTGGTCGCTAACGCTGGTGAAATCACCCTGCTGCCATCGGTAAAATTACAAATAGGCGATCGTGACAATTACGGTAACTACTGGGACGGTGGCAGCTGGCGCGACCGTGATTACTGGCGTCGTCACTATGAATGGCGTGATAACCGTTGGCATCGTCATGACAACGGCTGGCACAAAGGCTGGTACAAAGGCAGAGATAAAGCCTGGGAGCGCGGCTATCGTGCTGGCTGGAACGACCGCGATGACCACCGCGGCGGCTGGGGTCGCGGCCCGGGCGGGCGCGGTCACGGTCATGGACATGGCCATCACTAA SEQ ID NO: 34ATGAAGGAAATCGGCTTACCGTTATTGCTACTGACCGCGCTGGCCAGTCCGGCTTTTGCTGCAGACTGTCAGCCAAACGGCATTGGCGGCTCGTTTTGCATTAACGATGACGGTACGACTACCGACACGGTGCCTAACGAAGTCAACGGCATGGATACGTACTCGAATAATGGCGGCTATACCAGTTCCCTGCCCGATCGGTCAGGGGCGGATGAAGCACTGGAAGGTTCATCGCTGTCGACGCAGCAAGGCGTCGGCAGCGGACAGAGCGACAGTGCGCTGGCGGGTCGCGACTGGCATTCGCCCGCCAATCTGAATGATGGCGCCGCCACCTCCAGTATGAGCCTGCTGGATAAACCCTGA SEQ ID NO: 35ATGAATATGAAAAAACTGACGACCCTTTTGCTCACCGCCACCTTAGGTCTTGCCAGCGGCGCGGCCCTGGCGGCAGACACCGGCGCCCAGTCCAATAATGGCCAGGCCAACTCTTCCGCGGATGCCGGTCAGGTGGCGCCGGATGCCCGTGAGAACGTGGCGCCGAACAACGTGGACAATAGTCAGATCAACTCTGGCTCTGGGGGCACCACGGGCTCGACGATGACCCAGGATAATATGTCGAGCAATGAGGTACATAAAAACTCGATGTGTAAAGACGGCCGCTGTCCGGACACCGGTAAAAAACTGGACAACGGTGGCAATACGACCCAAGACAACAGCAAAACCGACGGCACCACCCAGTAA SEQ ID NO: 36ATGAAACACCGCATCGCTCTGCTTCTGGTCCTGACTTCACTTAGCGCCAGCGCCCTAGCCGCCTCTCCCTGCCAGGAAAAAGAGCAGGATATTCAACGAGAGATCAGCTACGCCGAAAAGCATCATAATCAAAGTCGCATTGATGGGCTAAATACCGCGCTACGTCAGGTTCGGGAAAACTGTAGCGACAGTAAACTCAAAGCCGATCATCAGCAAAAAATTGCCAAACAGCGGGAAGAGATCGCTGAACGTCAGCGCGATCTGCAGGAAGCCCGGAAGAAAGGCGATGCGGACAAAATTAACAAACGCCAGCATAAACTCAATGAAGCGCAACAGGAGTTAAAAACGCTGGAGTCTCGGGATTACTAA SEQ ID NO: 37ATGCGACTCATAACACGACACGTGAGAGAGGATATTATGAAAAAAGCAATGATTGCGTTATCGGCTATTCTGGTTGCGGCTCCGGTTTTTGCTGCGACAACACATGCAACAGATGATACCGTCGCGGCGGCGAATGCCAACGCCAACACCGCTAAAGAGAAGCTGCATCAGGCCCAGCACGAGGGCGAAGAGCAGCAGCTGAAGGCGAAACACGCCGCCGAAGGCAAGCAGGACAGCGTCGGCAGCCAGGTGAGCGAAGGCGCGCAGAAAACCTGGAACAAGACCAAAGAAGGCACCGAGAAGGGGTGGGATAAGACCAAAGAGGTCAGTGAAAAAGGCTGGAACGCCACCAAATCCGGTGCGGAAAAGGGCTGGGATAAAACCAAAACCGGCGCCGAAGAGTTAAAAAATAAAGTGACTGAATAA SEQ ID NO: 38ATGAAAAAGATGATTTCTCTGGCAGTAATTTTATCCTGTGTGCTGAGCGTCCCGGCCTTTGCCGATGGCCCGAACGACGGCCATCGCCCGGAGCAGCCCACGGTGTGGCAGAACGGTCCGGACCATGACGGGCATGCACCGCAGGGCGGACCTGACGCGCATCATCAGGGCGACCATGACCAGCGTGGCCCGGATCGCGACGGCCATGACAAACGCGATCTGGCACGTCATGAGCAGGACCATTTCGCCTGGCGCGGGAACGATTTCCGCAAAGGCCACCCGGCTCCGGCGCCGTTCCGTGGCGATGAATATCGCGTCCGCGACTGGAGCGACCGCGGCCTGCCGCCCCCGCCGGAAGGCCATCACTGGTCCTATATCGACGGTAACTATGTGCTGATCGCCGCGGCGACCGGGATCATCACCTCGATTCTGGTGAGCGGCGCCCTCGGCCACTAA SEQ ID NO: 39ATGAAAAAACCGACATCCGCCACCCGTGGCAAATCCGGCCGCAAGTCGCGTGAAGAGTTAAATCAGGAAGCTCGCGATCGCAAACGGCAGAAGAAACATCGTGGCCACGCGGCAGGCAGTCGCGCGAACGGCGGCGATGCGGCTTCAGCGGGTAAAAAACAGCGTCAGGCGCAAGATCCGCGCGTGGGTAGCAAAAAACCGATCCCGCTGGGCGTGAGCGAAAGCAGCGTTCCAGCTCCCAAGCAGCATAAACCAAAGAGCGAGAAACCTATGCTTTCACCGCAGGCTGAGCTGGAGTTGCTGGAGAATGATGAGCGCCTGGACGCGCTGCTGGAACGTCTGGAAGAGGGCGGCACCCTGAATGCTGAAGAGCAGAGCTGGGTGGACGCCAAACTGGATCGCATTGATGAGCTGATGCAGCAGCTCGGCCTCTCTTACGATGATGAAGATGAAGAAGAGGAAGAGCGTCAGGAAGATATGATGCGTCTGCTGAAGGGTGGAAACTAA SEQ ID NO: 40ATGGCGAGTAAGTTTCAGAACCGTTTAGTCGGGACAATCGTGCTGGTGGCGCTGGGGGTGATTATCCTGCCAGGGCTGCTGGACGGGCAGAAAAAGCATTACCAGGATGAGTTTGCCGCGATCCCGCTGGTACCGAAACCAGGCGATCGCGATGAACCGGATATGTTGCCGGCGGCAACCCAGGCGTTGCCTTCGCAACCGCCGGAAGGGGCGGCGGAAGAGGTGCGGGCGGGCGATGCCGCCGCGCCATCGTTAGATCCATCGCGTATTCCGGTGAACAGCAACAGCTTCGATGACGTTCAGGAGCCGGTGGTGGCCGCGAAACCGCAGCCCAAGCCGCAGCCGAAACCGCAGCCGCAACAGCAGGCCTCGACGCCAACGCCGCCGCCGGCTAAGCCACAGCAGCAACAGCCACCGCAGCAGCAGGCGGCCCTGCCGGCGCCGACCGGCAAAGCCTATGTGGTTCAGCTGGGCGCGTTGAAGAACGCCGATAAGGTGAATGAGATTGTCGGTAAACTGCGGGCCTCGGGTTTCAAAGTCTATACGTCGCCTTCGACGCCGGTACAGGGTAAAATTACCCGCATCCTCGTCGGCCCGGATGCGTCAAAAGACAAGCTGAAAGGCCAGCTGGGCGATCTGCAGCAGATCTCCGGGCTTAGCGGGGTGGTGATGGGCTTCACCCCGAACTGA SEQ ID NO: 41ATGGCACAACGAGATTATGTACGCCGCAGCCAACCGGCTTCTTCGCGGCGCAAAAAGAGCACGACCCGAAGCTCAAGGAATAAGCAAAGCAGCCTTCCGGCGATTTCACCGGCGATGGTGGCGATCGCGGCGGCTGTGCTGGTGGCCTTTATCGGTGGCCTCTATTTCATTACGCATCATAAGAAAGAAGAAGCGGAAGCGATGCAAAATCGCCAGGCCGCCGGCAACGGCTTGCCGCCCAAACCGGAAGAGCGCTGGCGCTATATTAAAGAGCTGGAAAGCCGCCAGCCTGGCGTCCGCGCGCCGACCGAACCGACCGCCGGTGGCGAAGTCATGAAACCGGAACAGCTGACCGACGAGCAGCGCCAGCTGCTCGCCCAGATGCAGGCCGATATGCGCCAGCAGCCGACCCAGCTGACCGAAGTGCCGTGGAACGAACAAACGCCGGCGCAGCGCCAGCAGACGCTTCAGCGTCAGCGTTTAGCGCAGCAACAGCAGCAGGCGCAGCAGCAACAGTGGGCGCAGACTCAGGCGCAGACCGTCCAACAGCAGCCGCCGCGCGTTCAGCAGCCGAAGCCGGTTCAGCAGCAACAGCCGAAGCAGACCGCGTCAAACCAGCAGCCGTACCAGGATCTGCTGCAGACGCCAGCGCATACCAATACCACGCAGCCGCGTACCCAGGCCGCGGCGCCGGTAACTCGGGTGGAAGAAGCGCCGAAAACCACCGCCGAGAAGAAAGACGATCGTAGCTGGATGATCCAGTGCGGCTCTTTTAAAGGCGCCGAGCAGGCCGAAACCGTCCGCGCTCAGCTGGCTTTCGAAGGGTTTGCTTCGCACATTACCACTAACAACGGCTGGAACCGCGTGGTTATTGGCCCGTTGAAAGGCAAAGAAAGCGCCAACGAGATGATCACCCGCCTGAAGATGGCTGGACACGCGAACTGCATTCGTCTCGCCGCCAGGGGTTGA SEQ ID NO: 42ATGAGCGCGGGAAGCACCAAATTTACCGTCAGCCGTATTGCGGCTCTTTCACTGGTTTCACTCTGGCTGGCCGGGTGTACCAACACCAATAATCCGCCTGCGCCGGTTAGCTCTGCCGGCGGCGCCGCCTCTTCCAGCACCAACTCCGGCATGCTGATTACGCCGCCACCCTCCGGCGTCAAGTCCGCTCCTCAGGCGCAGCCGATTCAGCCGATGCAGACCCAGACCATTCAGCCGGCGCCGGTGGCGCAGGAGCCGGTACAGACGGTAAATGGCCGGATCGTTTACAACCGCAAATATGGCGATATTCCGAAAGGTAGCTATACCGGCGGCAGTACCTATACGGTAAAACGCGGCGACACGCTATTCTATATCGCCTGGGTCACCGGCAACGATTTCCGCGACCTGGCGCAACGTAACAATATCCCGGCCCCGTACGCGCTGAACGTGGGGCAGGTACTGCAGGTCGGTAACGCCTCAGGCCAGCCGATCACCGGCGAAAACGCCGTTTCTCAGGCCAGCGCAAGAGCGAGCGGCGGTGCGACGACCAGCACAACTTCTGCACAAAAATCGACCGCGGTGGTTGCTTCACAACCGACTATTACGTATTCTGAATCTTCAGGTGAACAGAGTGCTACCAAGATGTTGCCTAATAATAAACCAGCGACCACAACCACAACGGTTGTCGCGCCGGTGACGGCACCAACAACGGTGAGCACAACCCAGCCGACTGCAAGCAGTACGTCAACCAGTTCGCCGATCTCAGCATGGCGCTGGCCGACTGATGGCAAGGTTATCGAGAACMAGCGGCGCGGAAGGCGGCAATAAAGGCATCGATATTGCAGGCAGTAAGGGACAGGCTATTGTCGCGACCGCCGATGGGCGCGTCGTCTATGCCGGTAACGCACTGCGCGGCTACGGTAATCTTATTATCATCAAACACAACGATGATTACCTGAGTGCCTACGCTCATAACGATACCATGCTGGTTCGGGAGCAACAGGAAGTCAAAGCGGGGCAGAAAATCGCTACCATGGGTAGCACCGGAACCAGCTCAACAAGATTACATTTTGAAATTCGTTACAAGGGGAAATCCGTCAACCCGCTGCAGTACTTACCGCAGCGATAA SEQ ID NO: 43ATGCGTAAGCAATGGCTGGGGATCTGCATAGCAGCGGGGCTGCTGGCGGCATGTTCGAGTGATGACGTGCAACAAAAAACGGTCAGTACTCCACAGCCGGCCGTCTGTAATGGCCCGACGGTTGAGATCAGCGGCGCCGATCCGCAGTATGAAACGCCGAACGCCACGGCGAATCAGGATTATGAGCGCGACGGTAAAAGCTACAAAATCGTTCAGGATCCGGCCAACTTTACTCAGGCCGGTTTCGCGGCGATCTATGACGCAGAACCCAACAGCAACCTGACCGCCAGCGGCGAAGCCTTCGATCCGACTCAGTTGACCGCAGCGCACCCGACGCTGCCGATCCCGAGCTACGCGCGGATCACTAACCTTGCCAACGGACGGATGATCGTCGTGCGGATTAACGATCGCGGTCCCTATGGCAACGATCGGGTCATCTCGCTTTCCCGCGCATCCGCTGACCGCCTGAACACCTCCAACAACACCAAAGTGCGCATCGACCCCATCATCGTCGCGCCTGACGGTTCGCTTTCCGGCCCGGGGATGGCCTGTACCACCGTCGCCAAACAGACTTACGCCCTGCCCGCCCGTCCGAATCTGGACGGTGGGGACGCCGCTGGCATGAGCCAGCCCGCGCCCACTGACGTTCGCCCGATCAGCAACAGCACGCTGACGCCGGCAGACAGCGTGGGCGCGCCGGTGAACAGCGGCGGTTTCCTCGGCGCGCCGACGCCCCTGAACAACGGCGTGCTGGAGAGTAGCGAACCAGCGGCAGCCGCCGCGACGGCTCCTGCCGCCGGCGCCACGCCAACAGCGCCAGTGACCGCGCCTGGCTCCATTCAGGGTAATGTGGTGCCCGCTGCGGCCACCGCCGCAGCCGCTGGCGCCGTGGCGGCCTCGTCCTCCGCGACCTCCAGCGCCAGCGGTAATTTTGTTGTCCAGGTGGGCGCAGTAAGCGACCAGACGCGGGCGCAGCAGTATCAGCAGCGCCTGAGCCAGCAGTTTTCTGTGCCAGGCCGGGTCATGCAAAACGGCGCGGTCTGGCGTATTCAGCTGGGTCCCTTTGCTGATAAAGCACAGGCCAGCGCCGTGCAGCAGCGCCTGCAAAGCGAAGCGCAGCTGCAGTCCTTTATTACTCGCGCCAACTAA SEQ ID NO: 44ATGGATGATTTCAAACCAGAAGACGATATGAAAGCCGATCGCAACGATCGTCGTGCTGGTCGTTCCCGTCAGTCTTCCGAGCGTGATGCCGATCCGCAGATCAATTTTGACGATGTTGATCTTGATGCCGATGAAGGCCGTCCGACGCGCGCTGGTAAGGCCCGTCGCGAGCGTGAAGAGGAAGAGTTCGAAGAAGAACTGGATGCGCAAGACGAGGAGATGCTCGAAGAGCAGCCTGTAGAGCGTCGTCCGCGCAAGCGTAAAAAAGCGCCGGCCAAACCGGCCTCCCGCCAGTACATCATGATGGGTGTGGGGATTCTGGTGCTGCTGCTGTTGATCGTGGGTATCGGTTCCGCACTGAAATCGCCATCATCTTCCAGCCAGCAGACCGCTTCCGGCGAGAAGAGCATTAATCTGTCTGACGACCAGTCCGCCAGCATGCCTGCTGCCGGCCAGGACCAGACTGCCGCCGCTAACAGCACCTCACAGCAGGACGTAACGGTACCGCCTATTGCCGCGAACCCGACGCAGGGCCAGGCAGCGGTTGCGCCGCAGGGCCAGCAGCGTATCGAAGTTCAGGGCGATCTGAACAATGCCTTGACCCAGCAGCAGGGCCAACTGGACGGCGCCGTGGCTAACTCGACGCTGCCGACTGAACCGGCTACCGTCGCGCCAATCCGGAATGGCGCCAATGGCACCGCGGCGCCGCGCCAGGCGACCGAGCGTCAGACAGCAGCGACCCCGCGTCCGGCTGAACGTAAGCATACCGTTATCGAAGCGAAGCCGCAGTCGAAGCCACAGGCCGTGGCGAAAACGCCGGTAGAATCGAAGCCGGTCCAGCCGAAGCATGTTGAAAGCACGGCGACCACCGCTCCGGCGAAAACGTCCGTCAGCGAAAGCAAACCGGTGGCCACCGCTCAGAGCAAACCGACCACGACGACCGCAGCGCCAGCGGCAACGGCAGCTGCGGCAGCGCCGGCAGCGAAGACCGGGAAGACGGCAGGTGACGTCAGCTCAATGAAAACTGCGCCGTCGGGTCACTATACTCTGCAGCTCAGCAGCTCCTCTAACTACGACAACCTCAACAACTGGGCGAAGAAAGAGAAGCTGGATAAATATGTTGTCTATGAAACGTCGCGTAACGGCCAACCATGGTACGTGCTGGTGAGCGGTATCTATGCATCGAAAGATGAAGCGAAACGTGCTGTCACCTCGCTGCCGGCGGACGTGCAGGCGAAAAATCCATGGGCAAAACCGCTGCATCAGGTTCAGGCTGACCTGAAATAA SEQ ID NO: 45ATGTCAAAGGCAACCGAACAAAACGACAAGCTTAAACGAGCGATCATCATTTCAGTCGCGCTGCACATCATTCTGATCGCGCTGCTGATCTGGAGTTCGTTTGACGAGCATCTGGATGCCTCTGCCGGCGGCGGCGGCGGATCGTCGATTGATGCCGTCATGGTCGATCCGGGGGCGGTGGTAAATAACTATAACCGTCAGCAACAGCAGCAGGCCAGCGCACGTCGCGCCGCTGAACAGCGTGAAAAACAGGCGCAGCAGCAGGCGGAAGAGTTACGTGAGAAACAGGCGGCGGAACAGGAACGGCTGAAACAGCTCGAACAGGAGCGGCTGCAGGCGCAGGAAGCGGCGAAAGAAGCGAAGGAGCAGCAGAAGCAGGCTGAAGAAGCGGCTGCCAAGGCCGCCGCGGCGGCAAAAGCCAAAGCGGACGCACAGGCAAAAGAAGCGCAGGAAGCCGCTGCCAAAGCGGCCGCCGAGGCGAAAGCGAAGGCGGATGCCCAGGCGAAAGCGGCAGAACAGGCGGCGGCCAAGGCGGCTGCTGACGCGAAAAAGCAGGCCGAAGCCGCTGCAGCGAAAGCCGCTGCCGAGGCGAAGAAACAGGCGGAAGCTGAAGCGGCGAAAGCTGCGGCCGAGGCGCAGAAGAAAGCGGAAGCGGCGGCTGCGAAGAAAGCGCAACAGGAAGCGGAGAAAAAAGCCCAGCAGGAAGCGGCTAAGCAGGCGGCAGCTGAAAAAGCGGCTGCCGAAAAAGCCGCTGAGAAAGCCGCCGCGCAAAAAGCGGCCGCTGAGAAGGCCGCCGCCGAGAAAGCCGCAGCCGCTGAAAAAGCGGCGGCAGCGAAAGCGGCTGCAGCAGAGAAGGCTGCAGCTGATAAAGCGGCCAAAGCGGCAGCAGCAAAAGCCGCGGCGGCGAAGAAAGCGGCGGCTGCGAAAGAAGCGGACGGCGTTGACAACCTGCTCGGCGATCTGAGTTCTGGTAAGAATGCGCCTAAAACAGGCGGTGGGGCCAAAGGAAACAATGCCTCCGCTGCCGGGAGTGGTAATACTAAAAACAGTGCCTCAGGGGCTGATATCAACAACTATGCCGGACAGATAAAATCGGCGATTGAAAGTAAGTTTTATGACGCATCGTCCTATGCGGGCAAAACATGTACCTTGCGTATCAAACTTGCTCCTGACGGCCTGTTGTTAAATATACAGTCCGAAGGTGGTGATCCTGCTCTGTGCCAGGCCGCTCTTGCCGCAGCCCGACAGGCTAAGTTTCCGAAACCACCTAGCCAGGCAGTATATGAAGTCTTCAAAAATGCGCCACTGGACTTCAAACCTCAGTGASEQ ID NO: 46ATGTTTTTTTTAAGTATTTTTTACATGGAGATGACAAAAGTGAAATTAAGCGCTCTGTTTATTGCCCTGATTCCTCTACTGGGCTCGCCGGTTATTCATGCAGAAACTACTGCTGCGCCGGTTCTGGAAAATCGCGCTGCGCAGGGAGATATCACCACTCCTGGCGGCGCGCGTCGTTTAACAGGCGATCAAACCGAAGCGCTGCGCGCCTCGTTAATCAATAAGCCAGCTAAAAACGTTATTTTGCTGATTGGCGATGGCATGGGTGATTCGGAAATTACCGCTGCGCGAAACTATGCCGAGGGGGCGGGCGGTTTCTTTAAAGGAATTGATGCTCTGCCGTTAACCGGGCAGTACACGCATTATTCGCTGGATAAAAAAACCGGGAAACCGGACTACGTGACCGACTCGGCGGCCTCCGCCACCGCCTGGACCACCGGCGTGAAGACTTATAACGGCGCGCTGGGCGTCGATATTCATGAGAATGCGCATCAGACCATCCTCGAGCTGGCGAAAGCGGCGGGGCTGGCCACCGGCAACGTTTCCACCGCCGAGCTGCAGGACGCCACCCCCGCGGCGTTGGTAGCGCATGTGACATCGCGTAAATGCTACGGCCCGACGGTCACCAGCGAAAAATGCCCCAGCAATGCGCTGGAAAAAGGGGGCAAAGGCTCCATTACCGAACAGCTGCTGAACGCCCGACCGGATGTCACCTTGGGCGGCGGCGCGAAGACCTTTACCGAAACGGCGACGGCGGGCGAGTGGCAGGGCAAAACCCTGCGCGAGCAGGCGCAAGCGCGCGGCTACCAGATTGTGACCGACGCGGCTTCTCTTGCCGCCGCGACGGAAGCCAGTCAGGATAAACCGCTGCTGGGACTCTTTGCCGATGGCAATATGCCGGTACGCTGGGAAGGGCCGAAGGCGTCTTATCACGGTAATATCGATAAGCCGCCGGTGACCTGTACGCCAAACCCGAAGCGTGACGCCTCGGTGCCGACGCTGGCGCAGATGACGGAGAAAGCGATTGACCTGCTCAGTCGCAACGAGAAAGGTTTCTTCCTGCAAGTCGAAGGCGCTTCCATCGATAAGCAGGACCATGCGGCGAATCCGTGCGGCCAGATCGGCGAAACGGTTGATCTTGACGAAGCGGTGCAGAAGGCGCTGGAATTCGCGCGAAAAGACGGTAATACCCTGGTGATCGTCACCGCCGACCATGCGCATGCCAGCCAGATCATCCCGGCGGATAGCAAAGCCCCGGGGCTGACCCAGGCTCTGAACACGCACGATGGCGCGGTGATGGTGATGAGCTACGGCAACTCTGAGGAAGAGTCGATGGAGCACACCGGCACCCAACTGCGCATTGCGGCCTACGGTCCGCATGCGGCTAACGTCGTAGGCCTGACCGATCAGACCGACCTGTTCACGACCATGAAAGCTGCCCTGAGTCTCAAATAA SEQ ID NO: 47ATGTCACTGCCGTTCAAACCCCATATTATCGCCCTGCTCTGTAGCGCTGGCTTACTCGCGGCGGCAGGAACACTCTATGTGCAAAGCCGAACCCCAGCGACGATCGCTGAACCGCCTGCGCAGCAAGCGCCAGCGCCCGCAGCGTCGACGACACAGCCGGTGGCCGCCACTTACACCCAGGCGCAAATTGATCAGTGGGTCGCCCCTATCGCGCTCTACCCGGACAGCCTGCTGTCGCAGGTGTTGATGGCCTCCACTTATCCCGACAACGTCCTGCAGGCGGTCCAGTGGTCCCAGGATAACCCCGCGATGAAAGGGGATGCGGCCGTGCAGGCGGTTGCCAGCCAGCCGTGGGACCCTAGCGTCAAATCTCTTGTCGCTTTCCCTGCCCTGCTGGCGATGATGGGCGAGAATCCGCCCTGGGTGGAAAATCTTGGCAATGCGTTTTTGGCCCAGCCGCATGATGTGATGGATTCAGTGCAGCGCCTGCGCGCCATTGCCCAACAAACCGGGACGCTGAAATCCACACCGCAGCAGAAAGTGATTGTCACCCCTGCCGCACCGGTTTCAGCCAGCAGCAGCACGGCAGCAACCGCAACCGCCCACACAGCGGCGCCTGCGCCCACGCAGGTCATTAAAATAGAGCCGACCAATCCACAGGTGGTCTATGTTCCCAGCTATAACCCCTCCACCGTCTATGGTACCTGGCCGAACAGCGCCTATCCGCCGGTCTATCTGCCGCCCCCTCCCGGGGAGCAGTTTACCGATAGCTTCGTCAAAGGCTTCGGGTACAGCCTCGGCGTGGCCACCACCTGGGCGCTGTTCAGCAGTATCGACTGGGATGATGATGACCATCACCATCACGATGACGACTACCACCACGGCGATTACTCGCATAATGGCGATAACATCAATATTAATGTAAATAATTTCAATCATATAACAGGAGAAAACCTGCCGGGAAACCACGTTAACTGGCAGCACAATCCTGCCTATCGCGGACACACACCGTATCCCGATAATACGGTAGCTCAGCGCTTCCATCAGACCAACGTTTCCGGCGGACTGAGCGCGACCCAACATGCGCCAGTCGATCGCGAAGCGCAGCGCCAGGCAGCGATGACCCAGCTGCAGCATAACGTACCGACGGCCACAGCGGGCAACCTGGCGGCAAACAACGCCTCACGCGACGCCCAGCGTCAGGCGGCCTCGGCGCAGCTGAAGCAAGCCACCCAACGCAGTAATTACCGCGGTTACGACAGTACGCCGACCCAACAGCAGCGTCGCGAGGCGGCAAAAACGCAGCTGAAAAACCCCACGCCGCAGCAACAGCAGCGTCGAGAAGCCGCCAGGAGCCACGAGCAGAACCGCACACCTCAGCAGCAGCAGCGCCGGCAGCAGTTCCAGTCCGCCACGCCAGCCCAGCGTCAGCAGACGCTCAGCCATCTGCGCGCCAACGCCCTTAGCGGCAACGAAAGCCGCGCCCCCTCCTGGCAAGCGCAGCAGGAACGAGGACTGCAGAGCCGCCAGTTTTCCGGCGTAAACCGCGAGTTACGCGATGGCACCAGAGAACGTCTTTCCGAACACCATGAACTGCGTCGCCGCTAASEQ ID NO: 48ATGTTTAAGTTTAAGGCTTCTTATGTCGCACTGGCGGCAGTATTAACCTCGTCGGTAGTTTATGCCGACCCCACAAGCTATACGCACTCTTCCGGCGCCACGGTTATCGATATTGAAAAGCCGAACGCCGCCGGTGTCTCCCATAACCTGTACCGCGACTTCAACGTCGGCGCCAATGGCACCATCCTCAATAACAGCGGCGATGATGTCAGCCACAGCACATTTGGCAATATCGCCCGCAACAATAATCTGACCGCCGGCAGCGCTTCGGTGATTTTGAACGAGGTGACCTCCAAAAACGCCAGTAGCCTGAAGGGCTTTATCGAAGTCAACGGTCAGAAAGCGGATGTGGTAATCGCCAACCCGAACGGCATCACCTGTTCCGGCTGTAGCTTTGTTAATACCAACAAGGCTATCCTGACCACCGGCAAGGTTAATATGACCGACGATGGCGCTATCGGCAGCTATACCGTAACGGGCGGCACCCTCACCATCGGCGAAAATGGCATGAACGCCGCCAACGGCTATGCGGTTCTGCTCGCCGACGCGATCAATATCAACGGTAAAGTGCAGGCCAACAACGCCCTGGTCAGCGCGGGCAACTTCACCATGGATAACAGCTCTGGCTCGGTGACCTCCGCTGGTAAAAAGGCCACCCTGATCCAGATGACGGTTAACCCGCAGTACAGCATCGACGTCAGCAGCCTTGGCGGCATTGAGGCCAACAGCATCAGCATGGTCGGCAATAACATCGGCTTTGGCGTACGTAATAAAGGCTCTATCGTCGCGAATAGTTCGCTGCAGCTCACCAGCAACGGTAATCTGCTGAACAAAGGCACGATCAAAAGCAACGGTCTGCTGAGTCAGGTCGCCACCGCCTCGGGCATCACCAATGACGGTAGCATCGCCGGCGCCTATTATTTAATGCTCTCCAGTGGCGATTATATCGTTAACACCGGTTCTCTCTCCGGCGGCCAGCTGATTGCCACCGCTAACGGCAACATCACCAACGGCGACTCAGGCACGATGACCGGCACCAGTGGATTAAGCCTGACCAGCGGCGGGAAAATCCGCAACGAAGAAAAAGCCTCCCTGCTGTCAAATAACCAGATTGCCGCCACGGCAATCGGTGATTTCCTCAATGAAGGCAAAATCAGCGCCAAACACACCAGCCTGACGTTTGTCGGCGACAGCTTTAAAAACACTGGCAATATTAACTCTACTGGCCAAACCACCATTCAGTCGCTTAAACAGGACGGCAGCGCCAATACGGGCGAGATCTATAACCTCGGCAATATCACCGGCGAAAATATCAATCTGCAGACCAATGGCACGCTGGCGCAAAGCAGCAGTGGTCGTATTGAGGCAACCAACGCCATTACCGCCCACAGCTACTGGCTGAACCAAAATGGTTATATGAATGCCGCCGATATCACCACCGATCACGGCGTAGTGAATAATTATGGCAATATTACTGCCAAAAATATTTCAATCACGACCTACTCAGATATCACCAACGAAGGGCAGATCAGCAGCACCGGCGACCTGACCTTAAATACCAAAAATAAAGGCGCGATCTACAATTATTCAACCCTCAGCGCGGGCGGCAACATGACGTTAACCGCCACCAAAGTGGTCAATGGTGGTAAAAGTTGCGGCATACTGGGCCTGGCGAAATGCGGCGTCGGGACGTTAACTGCTGACAAGCTGGTACTGAACTCATCGCAGAAATATGTTAGCGACATGGGTGGAAAACAGTATTTCAAGAGCACCGAAGTCAACACGGTGAAATAA SEQ ID NO: 49ATGATGGACAACCTACGCACGGCCGCCAACAGCGTCGTGCTCAAGATTATTTTCGGTATCATTATCGTCTCGTTCATTTTGACCGGGGTGAGTGGTTACCTGATTGGCGGTGGCAAAAACTATGCCGCAAAAGTGAATGGCCAGGAGATTGGCCGTGGGCAGTTTGAAAACGCCGTCGCCAGCGAACGTAACCGTATGCAGCAGCAGCTTGGCGATCAATTCTCCGAGCTGGCGGCGAACGAAAACTACATGAAAACCATGCGCCAGCAGGTGCTGAACCGCCTGATCGATGAGTCGCTTCTGGATCAGTATGCCCGCGAGCTGGGCCTCAGCATCAGCGATGAGCAGGTGAAGCAGGCGATCTTCCAGACCCAGGCGTTCCAGACGAACGGTAAGTTCGACAACCAGCGTTTCAGTGGTATTGTCGCCCAGATGGGGATGACCACCGATCAGTACGCCCAGGCGCTGCGTAACCAGCTGACCACGCAGCAGCTGATTAACGCCATTGCGGGTACCGACTTCATGCTGCCGGGCGAGTCCGATCAGCTGGCGGCGCTGGTATCTCAACAGCGGGTGGTCCGCGAAGCGACCATCAACGTAAATGCCCTGGCGGCAAAACAGACCGCCAGCGATGAGGAAATCAACGCCTTCTGGCAGCAGAATCAGGCCCGTTTTATGGCGCCGGAGCAGTTCCGCGTCAGCTACATCAAAATGGATGCCGCCAGCATGCAGGAGAGCGCCTCTGACGAAGAGATTCAGTCATGGTACGACCAGCACAAGGATCAGTTCACTCAGCCGCAGCGCAACCGCTACAGCGTGATTCAGACCAAAACTGAAGCCGATGCGAAAGCGGTACTGGCCGAGCTGCAAAAAGGAGCGGACTTCGCCACGCTGGCGAAAGAAAAATCGACCGATATTATCTCTGCCCGCAACGGTGGCGATATGGGGTGGATGGAAGATGCCTCTACCGTGCCTGAGCTGAAAGATGCCGGGCTGAAAGAGAAAGGCCAGCTGTCTGGCGTGATCAAATCCTCGGTTGGCTTCCTGGTAGCTCGTCTGGACGACGTCCAGCCGGCGCAGGTGAAGCCGCTGGCTGACGTGCGTAATGACATTGCGGCGAAAGTGAAGCAGGAAAAAGCGTTGGATGCTTACTACGCGCTGCAGCAGAAGGTGAGCGATGCGGCCAGCAACGATAATGAATCGCTGGCGAGCGCAGCGCAGGTCGCCGGGCTGAAGGTCGTAGAAACCGGCTGGTTTGGCCGCGATAACCTGCCGGAGGAGCTGAACTTTAAACCGGTCGCTGACGCTATTTTCAACGGCGGTCTGGTGGGTGAGAACGGCGCGCCGGGCAGCAACTCCGATATCATTACCGTTGACGGCGATCGCGCTTTTGTTCTGCGCATTAGCGAACACAAAGCCGAGGCGGTGAAGCCGCTGGCCGAAGTGAAGGCACAGGTTAGCGATATCGTTAAGCACAATAAAGCGGAACAGCAGGCGAAACTGGAGGCCGACAAGCTGCTGGCGGCGCTGAAAGACGGCAAAGGCGATGAAGCGATGAAGGCGGCTGGCCTGAGCTTTGGCGCGCCGCAGACGCTTTCTCGTACCGGCCAGGATCCGCTGAGCCAGCTGGCATTTACCCTGCCGCTGCCGCAGCAGGGTAAACCGGTCTACGGCGTGGGCAGCAATATGCAAGGCGATGTGGTGCTGGTAGCGCTGGATGAGGTGAAAGCCGGCAGCATGCCGGAAGAGCAGAAGAAGGCCATGGTTCAGGGGATCACCCAGAACAATGCCCAAATCGCTTTCGAAGCGCTGATGAGCAACCTGCGCAAGGCGGCGAAAATTAAGCTCGGCGACAGCATCGACCAGCAGCA GTAASEQ ID NO: 50ATGTTCAGGTTAAACCCTTTTATCCGGGCGGGATTGTCTGCGTCCGTCGTATCGTTGGCGTTTCCGGCTCTGGCCGATGTGAATGAAGAAACGCTGGTGGTGACCGCCTCGGCCACTGAACAGAATGTCAAAGACGCGCCGGCGAGCATCAGCGTCATCACCCAACAGGATTTACAACGCAAGCCTGTTCAGAACCTGAAAGACGTGCTGCGCGATGTGCCTGGGGTCCAGCTCACCAACGAAGGGGATAACCGCAAGGGCGTTAGCATCCGCGGTCTGAGCAGCAGCTATACCCTGATCCTGGTCGACGGCAAGCGCGTTAACTCGCGGAACGCCGTCTTCCGCCACAATGACTTCGACCTTAACTGGATCCCGGTGGATGCTATTGAGCGTATCGAAGTGGTGCGCGGCCCGATGTCCTCCCTCTACGGCTCCGATGCGCTCGGTGGGGTGGTCAACATTATTACCAAAAAAATCGGCCAGAAATGGACCGGGACGCTGAGTGCTGATACCACTATTCAGGAGCACCGCGATCGCGGGGATACCTGGAACGGCCAGTTCTTCACCAGCGGCCCGCTGATCGACGGCGTACTTGGAATGAAGGCCTACGGCAGCCTGGCAAAACGCGCCAAGGACGATCCGCAGTCATCCAGTAATGCCACCGGCGAGACGCCGCGCATCGAGGGCTTCACCAGCCGCGATGGCAATGTTGAATTCGCCTGGACGCCGAACGAAAACCACGATTTTACCGCAGGCTACGGCTTTGACCGTCAGGATCGCGATTCCGATTCCCTTGACCGCAACCGCCTTGAGCGGGAGAACTACTCTCTGAGCCATAACGGCCGCTGGGATATCGGCAATAGCGAGCTCAAGTTCTACGGCGAAAAGGTGGATAACAAAAATCCAGGGCAGAGCGGGACTATTACCTCGGAAAGCAATGCCATCGACGGCAAGTATGTCCTGCCGCTGGGCATGATTAACCAGCTGGTGACCTTCGGCGGCGAATGGCGCCACGACAAACTTAAAGATCCGGTCAACCTGAGCAGCGGCGGCCAGTCAACGTCGGCCAGCCAGTACGCCCTGTTTATCGAAGACGAATGGCGCATCATCGAGCCGCTGGCGCTGACCACCGGCATTCGTATGGACGACCATCAGACCTATGGCGATCACTGGAGCCCGCGCGCCTATCTGGTGTATAACGCCACCGATACCGTCACCGTCAAAGGCGGCTGGGCGACGGCGTTTAAAGCCCCGTCGCTGCTGCAGCTTAACCCCGACTGGACCACCAACTCCTGCCGCGGCTCGTGCAGCATCGTCGGTAACCCGGATCTGAAACCGGAAACCAGCGAAAGCTTCGAGCTCGGTCTCTACTACCGCGGGGAAGAGGGCTGGCTTGAAAATGTCGAAGGCAGCATCACCACCTTCCAGAATAATGTCGACGACATGATCGACGTTCTGCGCACCTCCAGCGCCAGCGAAGCGCCGGGCTACCCGAACTTTGTCGGCTGGAAAACTGTCAACGGCAAGCGCGTGCCGATCTTCCGCTATTTCAACGTCAACAAAGCCCGCATCAAAGGGGTGGAGACGGAGGTGAAGATCCCGTTTGGCGATGAGTGGAAGCTGACGGTGAACTACACCTACAACGATGGTCGCGATCTGAGCAATGGCGGCGACAAACCGCTGCAGACGCTGCCGTTCCATACCGCCAACGGCACGCTCGACTGGAAACCGCTGGACGACTGGTCCTTCTACGTGACGGCCAACTATACCGGCCAGCAGCGCGCGGTGAGCGCCACCGGCAAAACGCCGGGCGGCTACACCCTGTTTGACGTTGGCGCGGCATGGCAGGTGACCAAAAACGTGAAACTGCGCTCCGGGGTGCAGAACGTGGGTGATAAAGATCTGAGCCGGGACGACTACAGCTATACCGAAGAAGGCCGTCGCTACTTTATGGCGGTGGATTATCGCTTCTGA SEQ ID NO: 51ATGAACAGAGCCGCCACGCTGACCCTCAACGCGCCCCTGCTGATGCTCGTCGCTGCGCTGGCGCTTTCAACCCCTTTCACCGCCGGCGCCGCGCCGGCCTTTCTTGATTACGCCCAACAGCAAACCCAGCAATCTCAGGCGCAAGAAAAAAACGATGCCGCAAGCGCAAAACAAACACAAGAAAGCCGCCAGAGCGCAGATAATAAAAAAACCGGTACCAGCACCTCACAATTACAAAAAAGAATCACCAGCCAGCAGGCGGCGATTGCACAAAAAGATAAGCTTATACAGCAATTAAAAAAACAGCTTGCCGCTACGCCGCAAACGGATACTGCCGGAGCGAATGAGCAAGCGGCGTTGAATAAGAGAATTAATGAATTACAGGTCGCCTTAAGCGCCGCTACTGCAGAAAAAGAGGCATTAATAAAAAAAGCAGGCGTTGTGCAGAATAATAATCTACAGCAAAGCCAGGCCGCGGCGCGTCAGCAGATCCAGCAATTAACGACGCAGATTCAGCAAGCCGAAGCTGAAAATAAACGCCTCAGCGCCAGCTTTACCACGCTTAATAAAGATAAACACGCGCTAATGACCCAACTGGCCGCAACGGAAAAAGAGAAACAGGCCGCTCTTGAGCAGGTCAAAGCGCTTAACGCTGACAAACAGCCGCTGACGACCCGGCTGGCCGCCGCGGAAAAAGAGAAACAGGCCGTCCTCGAGCAGGTTAAGGCCCTTAACGCCGATAAACAGTCGCTGACTATTCGCCTCGCCGCTGCGGAGAAAGCGCAGCAGGCCGCTGTTGACCAGGCTAAAGCGCTTAACGCTGACAAACAGCCGCTGGCTACCCGACTGGCCGCCGCGGAAAAAGAGAAACAGGCCGTCCTCGAGCAGGTTAAGGCCCTTAGCGCCGATAAGCAGTCGCTGACTATTCGCCTCGCCGCTGCGGAGAAGGCGCAGCAGGCCGCTCTTGACCAGGCTAAAGCGCTTAACGCTGACAAACAGCCGCTGGCGACCCGGCTGGCCGCCGCGGAAAAAGAGAAACAGGCCGTCCTCGAGCAGGTTAAAGCCCTTAACGCCGATAAGCAGTCGCTGACTATTCGCCTCGCCGCTGCGGAAAAGACGCAGCAGGCTGCCCTCGATCAGGTCAAAGCCCTTAACGCCGATAAACAATCGCTGTCCACCCGGCTGGCCGCCGCGGATAAAGCGCCGCATGGCCCCGCTAACGACGCCGCTGCGCCAAAAAATGAGCCACCAGAGATGGCGGCCATAGTGGCAGCCTATCGCCTGCAGGCGGATAAAGACAACGCCCAGCTACGGATGAAAGAAGATGAAATCGAACTGCTGAGAACGCAGCTTTCTGTACAGTCCAAAACGCGCAGCGGCGAGAGCGCCGCCGCCAAACTCAGCGCATCGGGAGAACAGCAGGCTTATGCGATCGGCGCCTCGATGGGAAGCGAGGCGCTCAACGTCCTTACCACCCGTCGTACTCAGGGAGTTACCGTCGACGCAGGCCTGGTGCTGCAGGGCATCGAAGATGCCTTTCGCGGCCAGCTTCGTCTCGGAGAGCAGGAACGTAACAAGGCGCTGTTTGATGTGTCGCAGCAGGTTTTTCAGAACCTGAATAAAATAGAGCAGAAAAACATCAGTGCCGGCAAGAAATATCAGCAGGCGTTTGCGCGCAAAAAAGATGTGGTCTTTAAAGAGGGCGTCTACAGCCGCGTCGATTACCTGGGTAAAGGAAAAATAAGCGGTAATGACCTGGTTACCGTGGTGATCAAAGAGATGCTGACGGACGGGACGGTGATCAACGATATGGAAGCGAAAGATCAGGCGCTTACGCAAAAGCTGGATGCCTATCCCCCGGTGTTTCGCGAACCGCTGAAGCGTCTACAGAACCACGGCTCCGTGACGCTCGTCGTCCCGCCTGAAAAGGCCTATGGCAGTAAAGGATTACCGCCAAAAATCCCGCCAGGCGCCACCATGGTTTATTCCGTGCGGATAGTAGATAGCCAACCCGAGCCGGCAAAATAG SEQ ID NO: 52ATGAAAATCCTGTCCGTGCGTCACGCCGCCCTCCCGGCCCTGCTCTTGCCGCTCATTGCGGCAGCCCAGGCCGCTGATGAACAAACCATGGTGGTGACCGCCGCGCCAACCACGGTTTCTGAACTGGATACCCCCGCCGCCGTCAGCGTGGTGAATGGGGATGAGATGCGCCAGGCCGCGCCGCGCGTCAATCTCTCTGAATCGCTGGGCGCCGTGCCGGGCCTGCAGGTGCAGAACCGGCAAAACTATGCCCAGGATCTGCAGCTGTCGATTCGCGGCTTTGGCTCGCGCTCAACCTATGGCGTGCGCGGACTGCGCATCTATGTGGATGGCATTCCGGCCACCATGCCCGACGGCCAGGGGCAGACCTCAAATATTGATATCGGCAGCGTTGACACCATTGAGGTGCTGCGCGGCCCCTTCTCTGCCCTGTACGGTAACTCGTCCGGCGGGGTGATCAACGTCACCAGCCAGACCGGCACCCAGCCGCCCACCGTGGAAGCCAGCAGCTACTATGGCAGCTTCGGCACCTGGCACTACGGGATGAAAGCCACTGGCGCCGTTGGCGACGGCAGCCACGCAGGCGATGTGGATTACACGGTCTCAACCAATCGCTTCACCACCCATGGCTATCGCGATCACAGCGGCGCGCGCAAAAATCTGGCGAACGCCCGGCTGGGGGTGCGCATCAACGACGTCAGTAAGCTGACTCTGCTGCTGAATAGCGTGGATATCAAAGCCAATGACGCCGGTGGCCTGACCGCCGATGAATGGCGCGATAACCCGCGCCAGTCGCCGCGCGGCGACCAGTATAATACCCGCAAGAATACCCGACAGACCCAGGCCGGCCTGCGCTATGAGCGCCAGCTCAGTGCCCAGGACGATCTCAGCGTTATGATGTACGCTGGAGAACGTGAAACCACTCAGTTCCAGTCGATCCCGCGCGCGCCGCAGCTGAAGCCGAGCCATGCCGGCGGGGTGATCGACCTTACCCGTCACTACCAGGGGATCGATACCCGGCTGACCCATCGCGGAGAGCTGCTGGTGCCCGTCACGCTCACCGCCGGTCTCGACTACGAAAACATGAGCGAGCGGCGCAAAGGGTATGAAAACTTTGTGATGGTCAACGGCGCGCCGCAGTATGGCGAACAGGGCGCGCTGCGCCGTAACGAACGCAACCTGATGTGGAACGTCGACCCCTACCTGCAGACCCAGTGGCAGCTCACTGACAAACTCTCGCTCGATGCCGGGGTTCGCTACAGCTCGGTATGGTTCGACTCGAACGACTACTACATCACCCCAGGCAATGGCGATGACAGCGGTGATGCCAGCTATCACAAATGGCTGCCCGCGGGCTCGCTGAAATATGCCCTGACCGACGCGTGGAACGTCTATCTTTCCGCCGGCCGCGGCTTCGAGACGCCAACCATTAACGAACTCTCCTACCGCTCCGATAACCAGAGCGGCCTCAACTTCGGCCTGAAACCCTCCACCAACGACACGGTGGAGATCGGCAGCAAGACGCGGATCGGCAATGGGCTGTTCACCGCCGCCCTGTTCCAGACCAATACCGATAATGAGATTGTGGTCGACAGCAGCAGCGGCGGGCGCACCAGTTATAAAAACGCCGGCAAGACCCGCCGTCAGGGGATGGAGCTGGGGCTGGATCAGCAGTTTGGCGAGAGCTGGCGTCTGAAGGCGGCCTGGACCTGGCTGGACGCGACCTATCGCACTAACGTCTGCGACGACGCCAGCTGCAATGGCAATCGCATTCCGGGGATCGCGCGCAATATGGGCTACGCCTCCTTTGGCTATCAGCCGGAGCAAGGTTGGTACGCCGGGAGCGATATTCGCTATATGAGCGATATCATGGCCAATGACGAAAACACCGCCAAAGCGCCCTCCTGGACGGTGGTTGGCCTGACGACTGGCTATAAATGGAGCTACGGCAGGATGGATATGGATCTGTTCGGTCGCATCGACAACCTGTTCGACCGGGAGTACGTCGGGTCTGTCATCGTTAACGAGTCTAACGGACGTTACTACGAGCCTGCCCCGGGACGTAACTACGGCATCGGCCTGAACCTCGCCTGGCGCTTCGAATAA SEQ ID NO: 53ATGAAATACACGTCTCACTTCCCGCTGGGGATCGTCATTCCTCTGCTCGCCTGTAGCGTGCCGCTGCAGGCGGCAGAGAACATGACCGAACAATCGACGCCTGACGAGAGCGCCGCCACTGCCGAAAATCACGAGGAGACGATGGTCATAACCGCCGCCAGGCAGAACCTGCAGGCGCCGGGCGTGTCGACCATCACCGCAGAAGAGATCCGCAAACATCCCCCCGCCCGCGATGTGTCGGAGTTAATTCGTACGCAGCCCGGGGTAAACCTGACCGGCAACTCCACCAGCGGGCAGCGCGGCAACAACCGGCAAATTGATATCCGTGGCATGGGGCCCGAGAATACGCTGGTGCTGGTCGATGGTAAACCGGTGACCAGCCGTAACTCGGTGCGGTATGGCTGGCGCGGCGATCGTGACTCCCGCGGCGATACCAGTTGGGTGCCAGCGGAGATGATCGATCATATCGATGTGATCCGCGGCCCGGCGGCGGCGCGCTATGGTAATGGCGCGATGGGCGGGGTCGTCAACATCGTGACCAAACCGACCACGCGAGAATGGCACGGGTCGTGGAATACCTATATGAATGCTCCGCAGCACCGTAAAGAAGGGGCGACGAAACGTACTAACTTTAGCCTCAATGGTCCGCTGTCGGACAGTGTCAGCTTCAATCTCTGGGGTAATCTGAGTAAAACCCAGGCCGATGCACAGGATATTAACGCCGGGCATGAAGCGGAACGTACCGGTTCCTACGCCGGTTCTTATCCCGCCGGACGTGAAGGGGTGGTGAACAAAGATATTCACAGTAAGCTGCGCTGGGAGTTTGCCCCGATGCAGGCCCTGGAGTTTGAGGCCGGTTACAGCCGCCAGGGTAATCTCTATGCCGGCGACACACAAAACACCAATACCAGTACGCTGGTGAAGAGTATGTACGGGAAAGAGACCAACCGTCTCTACCGGCAAACTTACGGCGTAACATGGACCGGCGGCTGGGATAATGGCGTGACCAGCAACAGCTATGCCCAGTACGAACACACCCGTAACTCGCGAATGGATGAAGGGCTGGCGGGCGGTACGGAAGGGATCTTCTCCAGTAGCGAGTTTTCAGATATCGATCTGGCCGATGTCCTGCTACATAGTGAAGTGAATATTCCGTTTACGCTGGGGGTCGATCAGAATCTGACGCTGGGGGCAGAATGGAATCAGCAGCGGATGAAAGATGGCGTATCGACAACCCAGGCGCTCTCTTATGGCACTATCGATGGCGTATCGGCTACCGGTCGTAGCCCGTACTCCAGTGCCGAGATCTTCTCGCTGTTTACCGAAGATAATATGGCGCTAACGGACAGCACCATGCTGACACCCGCTCTGCGCTTCGATCACCACAGCATCGTCGGCAATAACTGGAGCCCCTCACTGAACCTGTCTCAGGAGCTGACGGACGACTGGACGCTGAAGCTGGGCATTGCCCGTGCTTACAAGGCGCCTAACCTCTACCAGTTGAACCCGAACTATATTCTCTACAGCAACGGTCAAGGCTGTTACGCCAGTAGTTCCGCCTGCTATCTGATGGGGAATAGCGATCTGAAAGCGGAGACCAGCGTTAATAAAGAGATTGGTCTTGAGTACAAGCATGATGGCTATCAGGCGGGGATCACCTGGTTCCGTAACGACTATCACAATAAGATTGAGTCAGGGTATGCGGCGGTGGGTACCGCCAGCAACGGCACCACCAATATCTATCAGTGGGAAAACGTACCAAAGGCGTTAGTGGAAGGCCTGGAAGGAACGCTGAATCTGCCGGTGGGGGAGGCGGTTAACTGGAGCAATAACCTGACCTGGATGCTGCAGAGCAAGAATAAGACGACCGGCGACCGGCTGTCAGTGATCCCGCAGTTTACCCTGAACTCGACTTTGAGCTGGCAGGTTCGTGAAGATCTCTCCCTGCAGAGCACCTTTACCTGGTATGGCCGACAGAAACCAAAACGCTTCAATTATAAGGGCGAGGCGGTCAGCGGCAGCGAACTAAACGAAGTCAGCCCATACAGCATTGTCGGCCTCAGTGCGACCTGGGATGTGAACAAAAATCTGAGCTTCACCAGCGGGATAGATAACCTGTTTGATATTCGCCACTACCGGGCAGGGAATGCGCAAACGACCGGCAACGCGACGACGGGAGCTTATCTGTATGGCGCGGGTGCCGAGACCTATAACGAATCGGGGCGGACCTTCTTTATGAGCGTTAATACTCATTTCTGA SEQ ID NO: 54ATGGAAAAAAACGCTTCTCTGCCTTTCGGCAGTTTCAACTCATTGGCATTGTTTACAGGTCTGTGTCTGGGAGCCTCGCCGGCAGCAGGCATCGCAGCGGAAAATTCGGTCAAAAATAGTGAAGAGACGCTGGTAGTGGAAGCCGCTCCGCCTTCACTCTACTCCCCCGGCGCTTCCGCCGATCCCAAGTTCAATAAACCGCTGGTCGATACCACCCGCACCATCACCGTGATCCCGGAACAGGTGATTAAAGATCAGGGCGTCACCAACCTGACTGACGCCCTCAAAAACGTTCCCGGCGTCGGGGCGTTTTATGCCGGGGAGAATGGCAGCTCAACCACCGGGGATGCCATCTTTATGCGCGGCGTGGATACCTCTAACAGCATCTATGTGGACGGCATTCGCGACATCGGTAGCGTGACGCGCGATACCTTCAATACCCAGCAGGTGGAAGTCATCAAAGGGCCCGCCGGCACGGACTATGGCCGCAGCGCGCCCTCCGGCTCGATCAATATGATCAGCAAGCAGCCGCGCCTTGACTCCGGGATCGACGGCTCGGCCAGCATCGGCAGCGCCTGGTCGCGCCGGGGCACTCTCGACCTGAACCAGGCGTTTAGCGACAACGCTGCGTTCCGTCTGAACCTGATGGGGGAAAAAACGCATGACGCTGGTCGGGACCGCATTGAAAACGAACGCTATGGCATCGCACCGTCGCTGGCCTTCGGCCTTGATACCCCAACTCGTCTGTATCTGAACTATCTGCACGTCCGGCAGAACAACACCCCGGATGGCGGGATCCCTACCGTCGGCCTGCCGGGCTATTCGGCGCCTTCGCCGAAGTATGCCGCACTCAACTCCGCCGGGAAGGTCGATACCAGCAATTTCTATGGCACCGACTCCGATTACGATAAATCTACTACCGACAGCGGTACCCTGCGCTTCGAACACGATCTGACGGAGAATACCACCGTGCGCAATACCACCCGCTGGTCGCGAGTGAAACAGGAGTATCTTTTGACCGCGGTGATGGGCGGCGCGAACAATATCACCGCCCCCGATATCAATGACGTCAACACCTGGAGCTGGTCGCGTCTGGTTAATACCAAAGATGTCAGCAACCGTATTCTGACCAACCAGACCAATATCACCTCGACTTTCAATACTGGCTCGATAGGCCATGACGTCAGCGCCGGCGTGGAGTTTACCCGGGAAAACCAGACCAACTATGGCGTTAACGCCAGGACCGCGCCGGCGGTGAATCTCTACCATCCGGTGAGCAACCTGTCGATTGGCGGGCTGGACAGAAACGGGGCGAACGCCAACGGCCAGACCGATACCTTCGGGATTTATGCCTTTGATACGCTGACGCTGACCGAGCGGATTGAGATCAACGGCGGGCTGCGTCTCGACAATTACCATACCAAATATGACAGCGCCACCGCCTGCGGCGGCAGCGGACGCGGGGCTATCGCCTGCCCGCCCGGACAGTCGACCGGCAGCCCGGTCACCACTGTCGATACCGCTAAATCCGGCAATCTGGTTAACTGGAAAGCCGGGGCGCTGTACCGCTTAACCGAGCAGGGCAATGTCTACGTCAACTACGCCATCTCACAGCAGCCGCCGGGAGGCAGCAGCTTCGCCCTGGCCGCCAGCGGCAGCGGCAACAGCGCTAACCGGACCGACTTTAAGCCACAGAAGGCGAAATCCAGCGAGCTGGGCACCAAGTGGCAAATCTTCGACAACCGTCTGCTGCTCAGCGCGGCGTTATTCCGCACCGATATTGAAAACGAAGTGGCCGCCAACGATGACGGAACCTGGTCGCAGTACGGCAAAAAGCGCGTGGAGGGGTATGAACTCTCCGCGACCGGAAACCTGACCCCGGACTGGACGATTATCGCCGGCTACACTCAGCAGCATGCGACAGTGACGGAGGGACAGAACGTTGCACAGGATGGATCTTCCGCCCTGGCCTACACCCCGAAACATGCCTTTACGCTGTGGACGCAGTATCAGGCCACCAGCGATCTGTCCGTCGGCGGCGGTGTGCGCTATGTCGGAAGCCTGCGCCGGGGCAGCGATGGTGCAGTCGGTACCCCGGATCACACCGAGGGCTACTGGGTTGCCGACGCCAAACTGGGCTATCGGGTCAACAGCAACCTCGATCTGCAGCTCAATATGTATAACCTGTTTGATACCGATTACGTGGCCTCCATCAACAAGAGCGGCTATCGCTATCATCCGGGCGAACCCCGGACCTTTATGCTGACGGCGAACGTCCATTTCT GASEQ ID NO: 55ATGGCGACTATGTACAAATCGACTCCGTCAGCAGCATGGTGTAAAAAACGCCTGCTGGTGACCTCTTTGTTTGCAGCAATTTATCAGACTTCTGCCATCGCAGCAGATACTTCCGCCGTTAGCGGCGAGGCGGTGGATGACACCTCGGAACAAATGACCGTCACCGCCCCCGCGCCGGTGCAGAAAGCCGGTAGCGAACACAGCATCAGCGCCCGGGAGCTGGAGAATAAAGGCGCTAACGATTTCGGCTCAATCATGCGCTATGAGCCGCTCATCAGCGCCACCGGGGCCAGCGGCGGCTCCGGCAACGGCAAAAGCGGCTTCGACCGCGGAGGTTACACCGGCTACAACATTCGCGGTATGGAGAGCAACCGCGTAGGCATCGACGTGGACGGTATCGCGCAACCCAACGCCACCGGCCGCGGCTACGTCGGCCGCGCCGGGCTCAACACCTTCGGCATCGGCCGCGATTATATCGACCCGTATATGTACGGCAGCGTTGATATCCAGTCCGGCGCCACCTCGACGGAAACGGCCAACAGCGCTATCGGGGGGAATGTCTCCTTCCGCCCGAAATCAGCGGATGATTACCTGCGCCCGGGCAAGACCAGCGCCTTCGGCTACCGCAGCGGTTACGACTCTGCGGATCGCAGCTGGCACAACGGGGTGACCGTCGCCGGCGGCGATGAGTTCCTGCGCGGGATTTTGGTCTATAGCCGCCGTGACGGCCAGGAAACTGAAAACAACAGCGGCACCGTCGACGCCTACCCGGCGAACTGGCACTCCGATGCTTTTCTGGCCTCCGGGATCTGGCAGCCTAACGATGAGCACAAGCTGACCAGCACCTTCGACTATTACCATAAAACCAACCACACCCACTACGATACCTGGGACTCCAGCGGCAACAGCACCATCGGCACCGCCAACCAGACCAGCCAGACCCGGCGCTGGGGCCTGAGCCTGAAGGATGACTGGACGCCGATGAACGACTACCTCGACAGCGTCTCCACAAAAATCTACTACCAGCATACCGAAGCCCATGACTGGACTTATATGCCGGACAGCGTCACCCGCAAAATGCAGACGGTGAACTCTAACTACGATACCGACACCTGGGGCCTGCAGACCGCGCTGGCGAAAACCCTGGGCCGCCACGATCTGAGCGCCGGTTTCAACGCCAGCACCAGCAAAACCCAGCGGCCGTTCAGCCAGTCGCCGATCCCCAGCGTTTACAGCGAGATCATGCAGCCGGAGGCAGACAGCCGCAGCTACACCCTCGGCGGCTTTGTCCAGGATAAGATCAACTTCGATCTCGACAGCCACAACTTCGCCGTTATTCCCGGCGTGCGCGTGGTGCATCAATCGACTAAGCCGGAAAATCTGTCCGATCTCGCCGCCAACAGCAGCGTGCTGAGCGAATCGTCGGTGGCGAATCTGTACGGCAAAAACAGCGATACCCAGGTTCTGCCGTCGTTGACCTTCCAGTACGACCTCACCCCGCGCCTGATGACCTACCTGCAGTACCAGCGCGGGGCGCAGTTCCCCAACGCCAGCCAGCTGTATGGCTCCTGGAACCTCGGCTCCAGCTACGCCGGCAGCCAGCAGTATGCCCTGATCGGCAATACCGATCTGAAGACGGAAACCAGCGATAATCTCGAGTGGGGGCTGAAAGGGGAAGTTACCGAAGGCATCACCCTGCGCACGGCGCTGTTCTACAACAGCTATAAGAACTTTATCGCCTATACCCGCTATACCCGCGCCAACAATCCGGGCCAGTTCACGAATGTGCCGTCGAACATCTACACCATTTATCAGGCGGAAAACCGCGATAAAGCCTATATCTACGGCGGTGAGATTAGCACCAAATTTAACTTTGGCACCTGGTTTGAGCAGGTGGACGGCCTGAGCGCCACCCTCGCCCTCGGCTATAGCGAAGGGAAATCGAAATCCAGCTACAGCGGCGATAAATACGTCGACCTCGACAGCGTGGCGCCAATGAAAGCCATCGTCGGCGTGGCGTGGGACGATCCGGCGAAACGCTACGGCACCGCCCTGACGGCGACCTTTGTCAAAGGGAAACAGGCGACCGCCACCAACCGCGAAAGCTACAGCAACAGCGGATCCGCCATCACCGATGCCAGCAGCGACTATATGCGCGTGCCGGGCTACGGCATGCTGGACTGGACCGCGTACTGGCAGGTGGCGAAAAACGTGCGCCTCAATGGCGGGGTCTACAACCTCACCGATCGTAAATACTGGGATTACCTGAGCAGCCGCAATATCGAGACCGGCACCAACCAGGACGCCAACGATAAAGCGCTGGCGGTGATGCCGGGCCGCACCTGGCAGCTGGGCGTCAACGTCGACTTCTGA SEQ ID NO: 56ATGGCGATGAAAAAGTTGCTCATAGCGTCGCTGCTGTTTAGCAGCGCGACTGTATACGGTGCTGAAGGGTTCGTGGTGAAGGACATTCATTTCGAAGGCTTGCAGCGTGTCGCTGTTGGTGCGGCCCTCCTCAGTATGCCAGTGCGTCCTGGCGATACGGTGACCGACGATGATATCAGTAACACTATTCGCGCGCTGTTTGCCACTGGCAACTTCGAGGACGTCCGCGTCCTGCGCGATGGTGATACCCTGCTGGTTCAGGTGAAAGAGCGTCCGACGATCGCCAGCATCACTTTCTCCGGCAACAAGTCGGTGAAAGATGACATGCTCAAGCAGAACCTTGAGGCCTCAGGCGTTCGGGTGGGCGAGTCGCTTGACCGCACGACCATCGCGGATATCGAGAAGGGTCTTGAAGACTTCTACTACAGCGTCGGTAAATACAGCGCCAGCGTCAAAGCAGTCGTTACGCCGCTGCCGCGTAACCGTGTCGATTTGAAGCTGGTCTTCCAGGAAGGCGTCTCCGCAAAAATTCAACAGATCAACATCGTCGGCAACCATGCGTTTTCGACCGATGAGCTGATCTCCCACTTCCAGCTGCGCGATGAGGTGCCGTGGTGGAACGTGGTCGGCGACCGTAAATACCAGAAGCAGAAGCTAGCGGGCGACCTTGAAACCCTGCGCAGCTACTACCTGGATCGCGGCTATGCCCGTTTCAACATCGATTCTACCCAGGTCAGCCTGACGCCGGATAAGAAAGGGATCTACATCACCGTCAACATCACCGAAGGCGATCAGTACAAGTTTTCCGGAGTGCAGGTGACGGGCAACCTCGCTGGCCATTCCGCGGAAATCGAAGCGCTGACTAAAGTTGAGCCAGGCGAACTGTACAACGGCGCGAAAGTGACCAAGATGGAAAACGACATCAAGAAACTGTTGGGTCGTTATGGTTACGCCTATCCGCGCGTGCAGTCGCAGCCGGAGATCAACGACAGCGATAAAACCGTTAAGCTGCACGTTAACGTCGACGCAGGCAACCGTTATTACGTGCGTAAAATTCGCTTCGAAGGCAACGACACCTCTAAAGATGCCGTACTGCGCCGCGAAATGCGCCAGATGGAAGGCGCATGGCTGGGCAGCGACCTCGTCGATCAGGGTAAAGACCGTCTCAATCGTTTAGGTTTCTTTGAAACGGTGGATACTGATACCCAGCGCGTGCCGGGCAGCCCGGACCAGGTCGACGTTGTCTACAAGGTGAAAGAGCGTAACACCGGTAGCTTCAACTTCGGTATCGGCTACGGCACCGAGAGCGGCGTCAGCTTCCAGGCGGGCGTTCAGCAGGATAACTGGTTAGGTACTGGCTATGCTGTCGGGATCAACGGTACCAAAAACGACTACCAGACCTATACCGAGCTGTCGGTGACCAACCCGTACTTCACCGTAGACGGTGTAAGCCTCGGCGGTCGTGTCTTCTATAATGACTTTGATGCGAACGATGCGGATCTGTCTGACTATACCAACAAAAGCTATGGTACAGACATTACGCTGGGCTTCCCGGTCAACGAATACAACACGCTGCGCGCCGGCGTCGGTTATGTGCATAACTCCCTGTCCAATATGCAGCCGCAGGTGGCAATGTGGCGTTACCTTAACTCGATGGGCCAGTATCCGGACAACACCAACGACCGGAACTCGTTCAGTGCGAATGACTTCACCTTCAACTACGGTTGGACCTATAACAAGCTTGACCGCGGCTTCTTCCCAACGGAAGGTTCGCGCGTCAACCTGAACGGTAAGGTGACCATTCCGGGCTCAGACAACGAGTACTACAAAGCGACGCTGGATACCGCGACCTACGTGCCGATCGACAACGATCATCAGTGGGTAGTACTGGGTCGTACGCGCTTTGGTTATGGCGATGGTATCGGCGGCAAAGAGATGCCGTTCTATGAGAACTTCTATGCCGGTGGTTCCAGCACCGTGCGTGGCTTCCAGTCGAACACCATTGGTCCGAAGGCGGTGTACTTCCCGGCAAGCAGTCGTCATGATGATGACGATAGTTACGATAATGAATGTAAGAGCACCGAATCCGCACCGTGTAAATCCGATGATGCGGTGGGCGGTAACGCGATGGCGGTGGCCAGCCTTGAGCTGATTACCCCGACGCCGTTTATTAGTGACAAATATGCGAACTCGGTCCGTACTTCCGTCTTCTGGGATATGGGTACCGTATGGGATACTCACTGGGATTCGAGCGCGTACGCTGGTTATCCGGATTACAGCGATCCGAGCAACATCCGTATGTCTGCGGGTATTGCCGTGCAGTGGATGTCGCCGTTGGGGCCGTTGGTCTTCTCCTACGCCCAACCGTTCAAAAAGTACGATGGAGACAAAGCCGAACAGTTCCAGTTTAACATTGGTAAAACCTGGTAA SEQ ID NO: 57ATGACAGATGTGACTATTAAAGCGCTGGCCTCAGAGATTCAGACCTCTGTGGATCGCCTGATACAGCAATTTGCTGACGCAGGCATCCGCAAATCGGCTGATGATTCTGTGACCTCGCAAGAGAAACAAACTTTGTTGACGCACCTGAACCGTGAACACGGCTCGGCGCCAGACAAGCTGACGTTACAGCGTAAGACGCGCAGTACGTTAAATATTCCAGGTACCGGTGGAAAGAGTAAATCGGTACAAATCGAAGTCCGCAAGAAACGCACCTTTGTGAAACGCGATCCGCAAGAGGCTGAACGCCTGGCCGCGGAAGAGCAGGCGCAGCGTGAAGCGGAAGAGCAGGCCCGTCGTGAAGCTGAAGAAGCAGCGAAACGCGAGGCGCAATTAAAAGCTGAACGTGAGGCCGCAGAACAAGCTAAACGTGAAGTCGCTGATAAAGCGAAACGTGAAGCTGCGGAAAAAGACAAAGTGAGCAATCAACATACCGACGAAATGACCAAAACCGCCCAGGCTGAAAAGATCCGTCGCGAGAACGAAGCCGCGGAATTGAAGCGCAAATCGGAAGAAGAAGCACGCCGCAAACTTGAAGAAGAAGCGCGCCGTGTAGCGGAAGAAGCACGCCGTATGGCTGAAGAAAACGAAAAAAATTGGTCTGAAACCTCAGACAGCCCGGAAGATAGCAGCGACTATCACGTCACCACATCACAGCATGCTCGTCAGGCTGAAGATGATAACGATCGTGAAGTCGAAGGCGGTCGCGGCCGTAGCCGTAGCAGCAAAGCGGCTCGTCCGGCGAAGAAAGGCAACAAACACGCTGAATCGAAAGCTGATCGTGAAGAAGCCCGCGCGGCCGTGCGCGGCGGTAAAGGCGGTAAGCACCGTAAAGGTTCCGCTCTGCAGCAGGGCTTCCAGAAGCCAGCGCAGGCCGTTAACCGTGACGTCGTAATCGGCGAAACCATCACCGTTGGCGAACTGGCTAACAAGATGGCGGTGAAAGGTTCTCAGGTCATCAAAGCGATGATGAAGCTGGGCGCCATGGCGACCATCAACCAGGTCATCGACCAGGAAACCGCACAGCTGGTTGCCGAAGAGATGGGCCACAAAGTTATCCTGCGTCGTGAAAACGAACTGGAAGAAGCCGTAATGAGCGACCGTGACACCGGCGCGGCGGCTGAACCGCGCGCACCGGTCGTGACCATTATGGGTCACGTTGACCACGGTAAAACCTCGCTGCTGGACTACATTCGTTCTACCAAGGTTGCCTCCGGCGAAGCGGGTGGTATTACCCAGCACATCGGTGCTTACCACGTCGAAACCGACAACGGCATGATCACCTTCCTGGATACCCCGGGCCACGCCGCGTTTACCTCCATGCGTGCTCGTGGCGCGCAGGCGACGGATATCGTGGTTCTGGTGGTGGCGGCAGACGACGGCGTGATGCCGCAGACTATCGAAGCTATCCAGCACGCTAAAGCGGCGCAGGTACCGGTGGTAGTGGCGGTGAACAAGATCGATAAGCCAGAAGCCGATCCGGATCGCGTGAAGAACGAACTGTCCCAGTACGGCATCCTGCCGGAAGAGTGGGGCGGCGAGAGCCAGTTCGTCCACGTTTCCGCGAAAGCGGGTACCGGCATCGACGACCTGCTGGACGCGATCCTGCTGCAGGCTGAAGTTCTTGAGCTGAAAGCGGTCCGCAACGGTATGGCGAGCGGCGCGGTCATCGAATCCTTCCTTGATAAAGGTCGTGGTCCGGTAGCTACCGTTCTGGTTCGCGAAGGTACTCTGCACAAGGGCGACATTGTTCTGTGCGGCTTCGAATATGGCCGTGTGCGCGCGATGCGTGACGAACTGGGTCGCGAAGTGCTGGAAGCGGGTCCGTCCATTCCGGTGGAAATCCTCGGCCTGTCCGGTGTGCCGGCTGCCGGTGATGAAGTGACCGTAGTGCGTGACGAGAAAAAAGCGCGTGAAGTGGCGCTGTATCGTCAGGGCAAATTCCGTGAAGTTAAGCTGGCGCGTCAGCAGAAATCTAAACTGGAAAACATGTTCGCTAACATGACCGAAGGCGAAGTTCACGAAGTGAACATCGTACTGAAAGCGGACGTACAGGGTTCTGTCGAAGCGATTTCCGATTCCTTACTGAAACTGTCTACCGACGAAGTGAAAGTGAAGATCATCGGTTCCGGCGTAGGTGGTATCACCGAAACCGACGCTACCCTGGCAGCAGCATCCAACGCGATTCTGGTTGGCTTCAACGTTCGTGCCGATGCCTCTGCGCGTAAAGTTATCGAAGCGGAAAGCCTGGATCTGCGTTACTACTCCGTCATCTATAACCTGATCGACGAAGTGAAAGCGGCGATGAGCGGCATGCTGTCTCCGGAACTGAAACAGCAGATCATCGGTCTGGCTGAAGTGCGTGATGTCTTCAAATCGCCGAAATTCGGCGCCATCGCGGGCTGTATGGTTACCGAAGGGACGATCAAACGTCACAACCCAATCCGCGTTCTGCGTGACAACGTGGTTATCTATGAAGGCGAGCTGGAATCCCTGCGCCGCTTCAAAGATGACGTTAACGAAGTCCGTAACGGCATGGAATGTGGTATCGGCGTGAAGAACTACAACGACGTTCGCGTTGGCGATATGATCGAAGTGTTCGAAATCATCGAAATCCAGCGTAGCATCGATTAA SEQ ID NO: 58ATGAAAAGAATGTTAATCAACGCAACTCAGCAGGAAGAGTTGCGCGTCGCCCTTGTTGATGGGCAGCGCCTGTACGACCTGGATATCGAAAGCCCCGGGCACGAACAGAAAAAAGCGAACATCTACAAAGGCAAAATCACCCGCATTGAACCCAGCCTTGAAGCCGCGTTTGTTGATTACGGCGCCGAGCGTCATGGTTTCCTCCCCCTCAAAGAAATCGCCCGCGAATACTTCCCCGCCAACTACAATGCGCATGGTCGTCCTAATATCAAAGACGTACTGCGGGAAGGTCAGGAAGTTATCGTGCAGATTGATAAAGAAGAACGCGGCAACAAAGGCGCTGCGCTCACCACCTTTATCAGCCTCGCGGGCAGCTATCTGGTACTGATGCCGAACAACCCGCGCGCCGGGGGAATTTCCCGCCGTATCGAGGGCGACGACCGTACCGAACTGAAAGAAGCGCTGGCGAGCCTGGAGCTTCCGGACGGCATGGGCCTGATCGTTCGCACCGCTGGCGTCGGCAAATCCGCCGAAGCCCTGCAGTGGGACCTGAGCTTCCGCCTGAAGCACTGGGAAGCGATTCAGAAAGCCGCGGAAAGCCGTCCGGCGCCGTTCCTGATCCACCAGGAAAGCAACGTCATTGTCCGCGCCTTCCGTGACTACCTGCGCCAGGACATCGGCGAAATCCTGATCGATAACCCGAAAGTGCTTGAGCTGGCGCGCCAGCATATCGCCGCGCTGGGTCGTCCGGATTTCAGCAGCAAAATAAAACTGTACACCGGTGAAATCCCGCTGTTCAGCCATTATCAGATCGAATCGCAAATTGAGTCCGCCTTCCAGCGCGAAGTGCGCCTGCCTTCCGGCGGGTCTATCGTTATCGATAGCACCGAAGCGCTGACCGCGATCGATATCAACTCCGCCCGCGCCACCCGCGGCGGCGATATCGAAGAGACAGCCTTCAATACCAACCTCGAAGCGGCTGACGAAATTGCCCGCCAGCTGCGTCTGCGCGACCTCGGCGGCCTGATCGTTATCGACTTCATCGATATGACCCCGGUCGCCACCAGCGCGCCGTGGAGAATCGTCTGCGCGAAGCCGTCCGTCAGGACCGTGCGCGCATTCAGATCAGCCATATTTCGCGCTTCGGCCTGCTGGAGATGTCCCGTCAGCGCCTGAGCCCGTCGCTGGGCGAGTCCAGCCACCACGTCTGCCCGCGCTGCTCCGGCACCGGCACCGTGCGTGATAACGAATCGCTGTCGCTCTCTATTCTGCGTCTGATCGAAGAAGAAGCGCTGAAAGAGAATACCAAAGAAGTCCACGCCATTGTTCCGGTACCGATCGCCTCCTATCTGCTGAACGAAAAACGTGCCGCAGTGAGCGCTATCGAATCCCGTCAGGGCGATGTGCGCGTTATTATCGTGCCAAACGACGAAATGCAAACGCCGCACTACTCCGTCCTGCGCGTGCGCAAAGGTGAAGAAACCTCAACGCTGAGCTATCTGCTGCCGAAGCTGCATGAAGAAGAAATGGCGCTGCCAGGCGACGATGAGCCGGCGGAGCGGAAACGTCCGGAACAGCCGGCCCTGGCCGCTTTTGTCATGCCAGATGCGCCGCCAGCCCCGATGCTCGAAGAGCCTGCCGCCGCGCCTGTCGCCGCAGCGGCACCGGTCGCGGCCGCCGCACCGGCGCAGCCTGGCCTGCTCTCACGCTTCTTCAGCGCGCTGAAGAATATCTTCTCTGGCGCCGAAGAGGCCAAACCGGCTGAAGTTCAGGTCGAGAAGAAAGCGGAAGAAAAACCGGAGCGTCAGCAGGAGCGTCGTAAACCGCGCGCCAACAACCGCCGCGACCGCAACGACCGCCGTGATAACCGCGACAATCGTGACAACCGCGATAACCGTGACAATCGCGACACCCGTGCGGACAATGCCGAGGGCCGTGAACCGCGCGAATCGCGTGAAGAGAACCGTCGCAACCGTCGCGAGAAGCCGTCGCAGAACGTGGAAGCCCGTGATGTTCGCCAAACCTCAGGCGACGACGCGGAGAAAGCGAAATCCCGTGACGAGCAGCAGCCGCGCCGCGAACGCACCCGCCGCCGCAGTGACGACAAACGTCAGGCGCAGCAGGAAGCCAAAGCGCAGACTCGCGAAGAGCCGGTTGTGCAGGAGACGGAGCAGGAAGAGCGTGTACAAACTCTGCCGCGTCGTAAACCGCGCCAGCTGGCACAGAAAGTGCGCGTTGAGTCCGCTGTCGTCGAGCCAGTTGCCGAGATCGTGCCAGAAGCCGTAGTGGCTGAAGTTATCGCTCCGCACAGCGAGCCGGTGAAAGCCGAGCTGCCGGCAGGGGTGGAGAGCGTGGCGGACCAGGACGAAAATGGCGAATCCCGTGAAGCGAACGGTATGCCGCGTCGCTCACGTCGCTCCCCGCGTCACCTGCGCGTCAGCGGTCAGCGTCGTCGTCGCTATCGTGACGAACGCTATCCGACCCAGTCGCCTATGCCGCTGACCGTAGCCTGCGCATCGCCGGAGATGGCTTCCGGTAAAGTCTGGATCCGCTACCCGGTGGTTCGTCCGCAGGATCAGCAGCCGGAAGAGGTTCAGGTTCAGGACGCCAGCGTCGCGAAAACTGTCGAGGCCGTAGCGGCCCCGGTCGCCGTCGTTGAAACCGTTACCGCTGCGCCGGTCACCGTCGAGCCGGCTACCATGGAACCAGTAACCGCTGAGCCGGTAGTCGTCGAGCCGGTAGCGGCCGCCGAGCCGCTGGTCGTTGATGCTGCGGAAGTTGTCGCGCCAGCAGCCGTCGAGCCAGCGCCTCAGGAGCCGGTCACCGAAGCACCGGCTGTCGAAGCGCCTCAGGCTATCGCGCCAGTGACGCTCGACGCCGAGCCGGTGGTGGTAGAACCTGAAGCGGTGGAAACGACGCCTGTCGTTGCAGCGCCAGTGGAAACTATCGCCCCGGTCGCAGAAACCGTGGAGCAAGCGCCAGTGACCGAAGCGGCCCCTGCCGAACCGGTCAAAGCCGAGCCCCCGGTGAGCAAGCCGGTCGTAGTGGCGGGTCATCGCCATGCCACCGCGCCAATGACCCGTGCGCCAGCTCCGGACTATGTCCCGGAAGCACCGCGTCATAGCACCTGGGTGCGCCCGCCGTTCGCCTTTGAAGGTAAAGGCGCCGCCGGTGGTCATAGCGCGACCCATAAAGCCACCGCTGAACCGACTCGCCCACAGCCCGTCGAGTAA SEQ ID NO: 59ATGCGCAAGCTCTCACTAAGTTTACTCACGCTGTCCCTCGGCGTTGCGCTGCTGCCGTTAGCGCAGGCGGCGACGACGCCTGCCCAGGAGCATCTGCTGGAGCAGGTCCGCCTCGGCGAGGCCAGCAATCGTGAAGACCTGGTGCGCCAGTCGCTGTACCGTCTGGAGCTGATTGATCCCAACAACCCGGAGCTGATTGCCGCGCGGATGCGCTATCTGCTGCGTCAGGGGGATGCCGCCGGGGCGCAAAAAGAGCTGGAACGACTGACGAAGCAGGCGCCGGACTCCCCGGAGCTGAAGGCGTCGCGCAATGAGATGAAAAGCAACACCGGCGAGGGCCGCCAGGCGCTGCAGCAGGCGCGACTGCTGGGCGTGGCCGGGAAGGTCGATGAAGCCATCGCCGCCTATGAAAAACTGTACGGCGGGGTGCCGGATGACGTTGACGTCGCCATTGAGTACTGGACGCTGGTGGCGCGCCTGCCGGCCCGCCATAGCGAAGGCGTCAGCCAGTTGAAAAAACTGAACGCCAGCGCGCCGGGCAACGTCAGCCTGCTGACTTCGCTGGCGAAGCAGATGTTCGCCGATAACAAACCGCAGGAGGGGTTCGCCTATCTGGCGGAGATGGCCCGATCGGCCTCGGGACGCGGTATCGCCGCCGATATGTGGTTCAGTGAGGTGAAAAGCATGCCGGTGAGTAAGGCCAGCGTGCAGGCGTTGCAGCAATTTCTTCTGCAGTTTCCCACCGGCTCGGTGGCGGCGAACGCCCGCGTTCTGCTCGACCAACAGCAGGCGCAGCTGCAGGATCCGACTTTCCGCGCCCGCTCGGAAGGGCTGGCGGCGGTCAAGTCCGGGAATACCACGCAGGCGGTCGCGGATCTGCAGAAAGCCGTTCAGGCCGACAGCCGCGACAGCGACGCGGTGGGCGCTCTCGGCCAGGCCTATTCCCAGCGCGGCGACCGCGCGCGGGCAGTGGCGCAGCTCAGTAAAGCGATTGCTATGGACCCTGACAGCCCGAACCGCGGCAAGTGGGACAGCCTGCTGCAAACTAACCGCTACTGGCTGCTGATAAAGCAGGGGGATAACGCCCTGAAAGCCGGCCAGCTTTCGCAGGCGCAGAACTATTATGCCCAGGCGCAGCGGGTCGATCGCACCGACAGCTATGCCGTGCTGGGGCTGGGGGACGTCGCGGCGGCGCGCAAAGAGGCGGCGGCGGCGGAGCGCTATTACCAGCAGGCGTTGCGCCTGGATCGCGGCAATAACCTGGCGGTGCGCGGCCTGGCCAACCTCTATCGCGCCGAATCGCCGGAGAAAGCCAGCGCCTGGATCGCCGGCCTCCCTCCCGCTCAGCGGCGGAGCATCGATGATATTGAGCGCAGCCTGACTAACGACCGGCTGGAGAAACAGGCGCAGGCTCTGGAGAGCCAGGGCAACTGGGCGCAGGCGGCGGAAGTTCAGCGTCGGCGCCTGGCGCTGGATCCGGACAGCGTCTGGATAACCTACCGTCTGGCGCGGGATCTGGTCAGCGCCGGCGAACGCCAGGAGGCCGACGCGCTGATGCGGACGATGGTCAACCGCCAGCCGCAGGACGCCGAACGGGTCTACGCCTCGGGACTCTACCTGTCGGGGAACGACCAGGACGATCTGGCTCTGGCGCAAATCGCCGCTCTGCCGCGCAGCGCGTGGACGGATAACATTCGTGAGCTCGAAGCGCGTTTGCAAAGCGACCGGGTGCTGCGCCAGGCCAACCAGCTGCGCGACAGCGGTAACGAAGCGCAGGCGATCGCCCTTATCCGACAGCAGCCCGCCTCGGTGCGCTATGACCTGACGCTCGCCGACTGGGCGCAGCAGCGCGGCGACAGCCAGACGGCGATTGCCAACTATCAGCGGGTGCTGCGCCAGGAGGCCGACAACGGCGATGCGCGCCTCGGCCTTGCGGAAGTCTACCTGGCCGAGGGCGATAAACCGGCCGCCCGGGCGCAGGTCATGCAGCTGAAAGGCGCAGAGACCGAATCCATGAACATGCAGCGGCGGGTGGCGCTGGCGCGAGCTGGCCTTGGCGATACCGCTGACGCGCAACGGATTTTTAATCAGATTGTGCCGCAGGCGAAGGCGCAGCCGCCCTCGATGGAGAGCGCGCTGGTGCTGCGCGATGCCGCGCGCTTTGCCACCCAGAGCGGGGCGCCGCAGCAGGCGCTGACGCACTACCGGGAAGCTATGGTGGCCTCCGGCATTACCCCCGCGCAGCCGCAGGATAACGATACTTTTACGCGGCTGACGCGCAACGACAGCCATGATGACTGGCTGAAGCGCGGGATCCGCAGCGATGCCGCCGACCTTTATCGTCAGCAGGATCTGAACGTCACCCTGGAACATGACTTCTGGGGTTCCAGCGGCACCGGCGGCTATTCCGACCTGAAGGCGCATACCACCATGCTGCAGATGGATGCTCCGCTGGCGGATGGCCGGATGTTCTTCCGCACCGACCTGGTCAATATGGATGCCGGCAGCTTTTCCACCCACAGCGACGGGAGCTACTCGCCCAGCTGGGGCACCTGCGGGGAGATCGCCTGTACCAGCGGCAGTAAAAATCAGACCGACAGCGGGGCCAGCGTGGCGGTCGGCTGGAAGAATGACACCTGGAGCGGGGATATCGGCACCACGCCGATGGGCTTCAATGTCGTCGATGTGGTGGGGGGGCTGAGCTACAGCAGCGACGTCGGGCCGGTGGGGTACACGGTCAACGTCCACCGGCGGCCTATCTCCAGCTCGCTGCTCTCCTTTGGCGGGCAGAAGGACAGCAGCAGCCATACCGGCGCCACCTGGGGCGGCGTCCGCGCCGACGGCGGCGGCCTGAGCCTGAGCTACGATCGCGGGGAGGCTCACGGCATCTGGTCCTCGCTGGGCGCCGACTCGCTGACCGGTAAAAACGTGGCGGATAACTGGCGCGTGCGCTGGATGACCGGGTACTACTACAAGGTCATCAACGAGAATAATCGTCGCGTCACCGTCGGCCTCAACAATATGATCTGGCACTACGACAAAGATCTCAGCGGCTACACCCTCGGCCAGGGCGGCTATTACAGCCCACAGGAGTATCTCTCGTTCGCCGTGCCGGTGACCTGGCGTCAGCGCACCGAGAACTGGTCCTGGGAGCTCGGCGGGTCGGTGTCATGGTCCCATTCGCGCACCCAGACGCAAGCCCGCTATCCGCTGCTGAACCTGATCCCGTCCGACTACCGGCAGCGCGCCAGCGAGCTGACGGAGGAGGGGAGCAGCAGCCATGGATTCGGTTACACCGCCAGAGCGCTGGTGGAGCGGCGGGTGACCAGCAACTGGTTCGTCGGCGCCGCGGTCGATATTCAGCAGGCGAAGGATTACACCCCGAGCCATGCGCTGCTTTACGTCCGCTACTCGGCGGCCGGCTGGCAGGGGGATCTGGATATGCCGCCCCAGCCGCTGGTGCCCTACGCCGACTGGTAG SEQ ID NO: 60ATGAGCCAGGAATACACCGAAGACAAAGAAGTCAAACTAACCAAACTCAGCAGCGGGCGCCGACTCCTTGAGGCGATGCTCATCCTTTGCTCCCTCTTCGCCATCTGGCTGATGGCGGCACTACTGAGCTTTAACCCCTCGGACCCCAGCTGGTCGCAAACGGCATGGCATGAGCCTATTCATAATTTAGGCGGCGCCCCCGGCGCGTGGCTTGCCGATACCCTCTTTTTCATTTTTGGCGTCATGGCCTACACCATCCCGGTGATCATCATCGGCGGATGCTGGTTTGCCTGGCGGCATCAGGAAAACGACGAATACATTGATTATTTTGCCGTTTCCCTTCGCCTCATCGGTGCGTTAGCCCTGATCCTGACCTCCTGTGGTCTGGCGGCGATTAACGCCGATGATATCTGGTACTTCGCCTCCGGCGGGGTGATCGGCAGCCTGCTGAGCACCACGCTGCAACCCCTGCTGCACAGCAGCGGCGGCACCATCGCCCTGTTGTGTATCTGGGCGGCCGGGCTGACGCTGTTCACCGGCTGGTCGTGGGTCAGCATTGCGGAAAAGCTGGGCGGCGGCATCCTGTCCGTTCTCACCTTTGCCAGCAACCGTACCCGTCGGGATGATACCTGGGTCGATGAAGGCGAATATGAAGACGACGAGGAAGAGTACGACGACGAAGAGGCGGCCAGGCCGCAGGAATCGCGTCGCGCCCGTATCTTACGCAGCGCGCTGGCGCGGCGTAAGCGTCTGGCCGAGAAGTTTACCAACCCTATGGGGCGTAAAACCGACGCTGCGCTTTTCTCCGGCAAACGGATGGATGACGGCGAAGAGGTGGTGCAATACAGCGCCAGCGGGGCGCCTGTTGCCGCCGACGATGTACTGTTTTCCGGCGCCAGCGCCGCGCGTCCCGCAGAGGATGATGTGCTGTTCTCCGGCGCCAGCGCCGTGCGCCCGGGCGATTTCGACCCTTACGATCCGTTGTTGAATGGCCACAGTATCGCTGAGCCGGTAAGCGCAGCGGCGGCGGCTACAGCCGCGCCGCAGGCGTGGGCAGAATCACCGGTGGGCCATCACGGCGCTGCGCCAGCTTATCAGCCGGAAGCCAGCTATCCGCCGCAGCAGGCCTATCAGCCTGAACCCGCTCCGTTCCAGCAGGCCTATCAGCCTGAACCCGCTCCGTTCCAGCAGGCTGCTTATCAGCCGCCAGCGGGGCAAACCGCACCGCAGGCGTATCAGCCTGAGCCAGCGCCGTATCAACAGCCGGTTTACGATCCGCGTGCCGGTCAACCTGCGCCGCAGGCCTATCAGCCTGAGCCAGCGCCGTATCAGCAGCCGGCTTACGATCCGTATGCCGGTCAACCTGCGCCGCAGGCCTATCAGCCTGAACCTGCGCCGTATCAGCAGCCGGCTTACGATCCGCATGCCGGTCAACCTGCACCGCAGGCCTATCAGCCTGAGCCAGCGCCGTATCAGCAGCCGGCTTACGATCCCTATGCCGGTCAACCTGCGCCGCAGGCCTATCAGCCGGAGCCAGCGCCGTATCAGCAGCCAACTTACGATCCCTATGCCGGTCAGCCTGCGCCTCAGACCTATCAGCAGCCGGCTTACGATCCGAATGCCGGTCAGCCCGCGCCGCAGCCGTATCAGCCGGAGCCAGCGGCGTATCAGCCGCAAAGCGCGCCAGTTCCCCCACCGGAGCCAGAGCCCGAGGTCGTGCAGGAGGAAGTGAAACGTCCGCCGCTCTATTATTTCGAGGAAGTGGAAGAGAAGCGGGCGCGCGAACGCGAGCTGTTGGCCTCCTGGTATCAGCCAATTCCTGAGCCGGAAAGTCCGATTGCCACTAAACCGCTGACGCCGCCGACCACTGCGTCCAAACCGCCAGTGGAGACAACCGTAGTCTCTGCGGTAGCGGCTGGGGTGCATCAGGCTACCGCCGCCAGCGGCGGCGCGGCGGCAGCAACCTCGTCCACTGCCGCATCCGCTGCGGCTACGCCATTGTTCAGCCCGGCGTCCAGCGGCCCAAGGGTTCAGGTGAAAGAGGGCATCGGTCCAAAACTACCGCGGCCCAATCGCGTGCGTGTTCCTACGCGTCGGGAACTGGCCTCCTACGGCATCAAGCTACCGTCGCAGCGGGAGGCGGAACAGCGCGCGCGGCAGGCGGAGCGCGATCCGCATTATGATGATGAGCTGCTCTCGGATGAGGAAGCGGATGCTATGGAGCAGGATGAACTGGCTCGCCAGTTCGCCGCCACCCAGCAGCAGCGCTACGGTCATCGCTGGGAAGACGATAACGCGACTGATGACGATGAGGCCGACGCCGCGGCGGAAGCGGAGCTGGCGCGTCAGTTTGCCGCTACCCAGCAGCAGCGGTACGCTACCGAGCAGCCGCCGGGCGCCAACCCGTTCTCGCCGGCAGATTATGAATTCTCGCCGATGAAAACGTTGGTCAATGACGGCCCGAGCGAACCGCTGTTTACGCCGACGCCGGAAGTCCAGCCGCAGCAGCCGGCCCAGCGCTATCAACAACCGGCGGCCGCTCCGCAGCAGGGTTATCAACCTGCGCAGCATCAGCCGATACACCATCAGCCTGTGCCGCCACAGCCGCAGTCCTATCCGACTGCGTCGCAGCCCGTACAGCCGCAACAACCGGTTGCCCCGCAGGGGCATCAGCCTGCCGCCCCTGCGCCGCAGGAGAGCCTGATCCACCCGCTGCTGATGCGCAATGGCGATAGTCGACCGCTGCAAAAGCCGACCACGCCACTGCCGTCGCTGGATCTGCTTACCCCGCCGCCGAGTGAAGTCGAGCCGGTGGATACCTTTGCTCTCGAGCAGATGGCACGCCTGGTGGAAGCGCGACTCGCTGATTTCCGCATTAAAGCGGATGTGGTGAACTACTCACCGGGGCCGGTGATCACCCGCTTCGAACTGAATCTGGCGCCTGGCGTTAAGGCCGCACGGATCTCTAACCTGTCACGGGACCTGGCGCGATCGCTGTCAACGGTCGCCGTGCGCGTGGTGGAGGTGATCCCGGGCAAACCGTATGTCGGGCTTGAGCTGCCGAATAAAAAACGCCAGACCGTCTACCTGCGTGAAGTGCTCGACAACGCCAAGTTCCGTGATAACCCATCTCCGCTCACCGTGGTGTTGGGTAAAGACATCGCTGGCGATCCGGTAGTAGCCGATCTGGCGAAAATGCCGCATCTGCTGGTGGCCGGTACCACCGGTTCCGGTAAGTCTGTTGGCGTCAACGCCATGATCCTCAGCATGCTCTACAAGGCGCAGCCGGAAGATGTGCGTTTCATTATGATCGACCCGAAAATGCTCGAGCTGTCGGTCTACGAAGGAATTCCGCACCTGCTGACGGAAGTGGTCACCGACATGAAAGACGCCGCCAATGCGCTGCGCTGGAGCGTCAATGAGATGGAGCGCCGCTACAAGCTGATGTCGGCGCTGGGCGTGCGTAACCTCGCGGGCTACAACGAGAAGATCGCCGAAGCCGCGCGCATGGGACGTCCGATCCCGGATCCGTACTGGAAGCCTGGCGACAGCATGGACGCCGTACATCCGGTGCTGGAAAAACTGCCGTACATCGTGGTGCTGGTGGATGAATTCGCCGATCTGATGATGACCGTCGGCAAAAAGGTGGAAGAGCTGATCGCTCGCCTGGCGCAGAAAGCGCGCGCGGCGGGGATCCACCTGGTGCTGGCGACACAGCGTCCGTCGGTAGATGTTATTACCGGCCTGATTAAGGCCAACATCCCGACGCGCATCGCCTTTACCGTGTCGAGTAAAATTGACTCACGTACCATTCTCGATCAGGGCGGCGCGGAATCGCTGCTGGGTATGGGGGATATGCTTTACTCCGGGCCGAACTCTACCACGCCGGTGCGTGTCCACGGGGCGTTTGTGCGCGACCAGGAAGTCCACGCCGTGGTTCAGGACTGGAAAGCCCGCGGTCGCCCGCAATATGTGGATGGCATTACCTCCGACAGCGAAAGCGAAGGCGGCGGTGGCGGCTTCGACGGCGGGGAAGAGTTGGATCCGTTGTTCGATCAGGCAGTCAACTTTGTGACCGAGAAGCGCAAAGCGTCGATTTCCGGGGTTCAGCGTCAGTTCCGCATCGGCTATAACCGTGCCGCGCGTATTATCGAACAGATGGAAGCGCAGGGTATCGTCAGCGAGCAGGGCCATAACGGTAACCGCGAAGTGCTGGCGCCGCCGCCCTTTGAATGA SEQ ID NO: 61AUGAAGAAGUUAGCUUUACUCUCCGCCGUAAUGACGCUUGGAAUGUCGUCAUGGGCUUUUGCUGCCGACAACCCGCCGCCGCCGCCGGAAAAAGGCGCGCAGCAUCAGGGUAAACCGCCGGUGAAAAACGGCCAACACGAAGGUAAGCAAGCGCAAUACAACAGAAAACAGCCACAACGAGACGGCAAACAGCCGCAGCACGACGGUAAACAGCCGCAGCACAACGGCAAGCAGCCGCCAAAAGGGAGCGAGCACAGCGGGAAACCGCUGCCGCCGAAAGCGUAA SEQ ID NO: 62AUGAAACGUUACGCAACCGCACUGCUCUUUUGCACUCUGUCGCUGACCAGCCUGGCCGCUCGCGCCGAUAUUAUCGAUGACGCGAUCGGCAAUAUUCAGCAAGCCAUUAACGACGCCUAUAACCCCGGCAGCAGUCGCUCCGAUGACGACGACAGAUACGAUGACGAUGGCCGGUAUGAUGACGGGCGCUAUCAGGGGAGCCGUCAGCAGAGCCGUGACAGUCAGCGCCAGUAUGACGAGCGGCAACGCCAGCUGGACGAGCGCCGCCGCCAGCUGGAUGAACGCCAGCGUCAGCUCGACCGCGAUCGUCGUCAGUUAGAAAGCGACCAGCGUCGUCUGGAUGAUAGCUACUGA SEQ ID NO: 63AUGUUCAGGUCACUGAUUCUGGCAGCAGUACUGCUGGCCGCAGGGCCACUGGUCGCUAACGCUGGUGAAAUCACCCUGCUGCCAUCGGUAAAAUUACAAAUAGGCGAUCGUGACAAUUACGGUAACUACUGGGACGGUGGCAGCUGGCGCGACCGUGAUUACUGGCGUCGUCACUAUGAAUGGCGUGAUAACCGUUGGCAUCGUCAUGACAACGGCUGGCACAAAGGCUGGUACAAAGGCAGAGAUAAAGCCUGGGAGCGCGGCUAUCGUGCUGGCUGGAACGACCGCGAUGACCACCGCGGCGGCUGGGGUCGCGGCCCGGGCGGGCGCGGUCACGGUCAUGGACAUGGCCAUCACUAA SEQ ID NO: 64AUGAAGGAAAUCGGCUUACCGUUAUUGCUACUGACCGCGCUGGCCAGUCCGGCUUUUGCUGCAGACUGUCAGCCAAACGGCAUUGGCGGCUCGUUUUGCAUUAACGAUGACGGUACGACUACCGACACGGUGCCUAACGAAGUCAACGGCAUGGAUACGUACUCGAAUAAUGGCGGCUAUACCAGUUCCCUGCCCGAUCGGUCAGGGGCGGAUGAAGCACUGGAAGGUUCAUCGCUGUCGACGCAGCAAGGCGUCGGCAGCGGACAGAGCGACAGUGCGCUGGCGGGUCGCGACUGGCAUUCGCCCGCCAAUCUGAAUGAUGGCGCCGCCACCUCCAGUAUGAGCCUGCUGGAUAAACCCUGA SEQ ID NO: 65AUGAAUAUGAAAAAACUGACGACCCUUUUGCUCACCGCCACCUUAGGUCUUGCCAGCGGCGCGGCCCUGGCGGCAGACACCGGCGCCCAGUCCAAUAAUGGCCAGGCCAACUCUUCCGCGGAUGCCGGUCAGGUGGCGCCGGAUGCCCGUGAGAACGUGGCGCCGAACAACGUGGACAAUAGUCAGAUCAACUCUGGCUCUGGGGGCACCACGGGCUCGACGAUGACCCAGGAUAAUAUGUCGAGCAAUGAGGUACAUAAAAACUCGAUGUGUAAAGACGGCCGCUGUCCGGACACCGGUAAAAAACUGGACAACGGUGGCAAUACGACCCAAGACAACAGCAAAACCGACGGCACCACCCAGUAA SEQ ID NO: 66AUGAAACACCGCAUCGCUCUGCUUCUGGUCCUGACUUCACUUAGCGCCAGCGCCCUAGCCGCCUCUCCCUGCCAGGAAAAAGAGCAGGAUAUUCAACGAGAGAUCAGCUACGCCGAAAAGCAUCAUAAUCAAAGUCGCAUUGAUGGGCUAAAUACCGCGCUACGUCAGGUUCGGGAAAACUGUAGCGACAGUAAACUCAAAGCCGAUCAUCAGCAAAAAAUUGCCAAACAGCGGGAAGAGAUCGCUGAACGUCAGCGCGAUCUGCAGGAAGCCCGGAAGAAAGGCGAUGCGGACAAAAUUAACAAACGCCAGCAUAAACUCAAUGAAGCGCAACAGGAGUUAAAAACGCUGGAGUCUCGGGAUUACUAA SEQ ID NO: 67AUGCGACUCAUAACACGACACGUGAGAGAGGAUAUUAUGAAAAAAGCAAUGAUUGCGUUAUCGGCUAUUCUGGUUGCGGCUCCGGUUUUUGCUGCGACAACACAUGCAACAGAUGAUACCGUCGCGGCGGCGAAUGCCAACGCCAACACCGCUAAAGAGAAGCUGCAUCAGGCCCAGCACGAGGGCGAAGAGCAGCAGCUGAAGGCGAAACACGCCGCCGAAGGCAAGCAGGACAGCGUCGGCAGCCAGGUGAGCGAAGGCGCGCAGAAAACCUGGAACAAGACCAAAGAAGGCACCGAGAAGGGGUGGGAUAAGACCAAAGAGGUCAGUGAAAAAGGCUGGAACGCCACCAAAUCCGGUGCGGAAAAGGGCUGGGAUAAAACCAAAACCGGCGCCGAAGAGUUAAAAAAUAAAGUGACUGAAUAA SEQ ID NO: 68AUGAAAAAGAUGAUUUCUCUGGCAGUAAUUUUAUCCUGUGUGCUGAGCGUCCCGGCCUUUGCCGAUGGCCCGAACGACGGCCAUCGCCCGGAGCAGCCCACGGUGUGGCAGAACGGUCCGGACCAUGACGGGCAUGCACCGCAGGGCGGACCUGACGCGCAUCAUCAGGGCGACCAUGACCAGCGUGGCCCGGAUCGCGACGGCCAUGACAAACGCGAUCUGGCACGUCAUGAGCAGGACCAUUUCGCCUGGCGCGGGAACGAUUUCCGCAAAGGCCACCCGGCUCCGGCGCCGUUCCGUGGCGAUGAAUAUCGCGUCCGCGACUGGAGCGACCGCGGCCUGCCGCCCCCGCCGGAAGGCCAUCACUGGUCCUAUAUCGACGGUAACUAUGUGCUGAUCGCCGCGGCGACCGGGAUCAUCACCUCGAUUCUGGUGAGCGGCGCCCUCGGCCACUA ASEQ ID NO: 69AUGAAAAAACCGACAUCCGCCACCCGUGGCAAAUCCGGCCGCAAGUCGCGUGAAGAGUUAAAUCAGGAAGCUCGCGAUCGCAAACGGCAGAAGAAACAUCGUGGCCACGCGGCAGGCAGUCGCGCGAACGGCGGCGAUGCGGCUUCAGCGGGUAAAAAACAGCGUCAGGCGCAAGAUCCGCGCGUGGGUAGCAAAAAACCGAUCCCGCUGGGCGUGAGCGAAAGCAGCGUUCCAGCUCCCAAGCAGCAUAAACCAAAGAGCGAGAAACCUAUGCUUUCACCGCAGGCUGAGCUGGAGUUGCUGGAGAAUGAUGAGCGCCUGGACGCGCUGCUGGAACGUCUGGAAGAGGGCGGCACCCUGAAUGCUGAAGAGCAGAGCUGGGUGGACGCCAAACUGGAUCGCAUUGAUGAGCUGAUGCAGCAGCUCGGCCUCUCUUACGAUGAUGAAGAUGAAGAAGAGGAAGAGCGUCAGGAAGAUAUGAUGCGUCUGCUGAAGGGUGGAAACUAA SEQ NO: 70AUGGCGAGUAAGUUUCAGAACCGUUUAGUCGGGACAAUCGUGCUGGUGGCGCUGGGGGUGAUUAUCCUGCCAGGGCUGCUGGACGGGCAGAAAAAGCAUUACCAGGAUGAGUUUGCCGCGAUCCCGCUGGUACCGAAACCAGGCGAUCGCGAUGAACCGGAUAUGUUGCCGGCGGCAACCCAGGCGUUGCCUUCGCAACCGCCGGAAGGGGCGGCGGAAGAGGUGCGGGCGGGCGAUGCCGCCGCGCCAUCGUUAGAUCCAUCGCGUAUUCCGGUGAACAGCAACAGCUUCGAUGACGUUCAGGAGCCGGUGGUGGCCGCGAAACCGCAGCCCAAGCCGCAGCCGAAACCGCAGCCGCAACAGCAGGCCUCGACGCCAACGCCGCCGCCGGCUAAGCCACAGCAGCAACAGCCACCGCAGCAGCAGGCGGCCCUGCCGGCGCCGACCGGCAAAGCCUAUGUGGUUCAGCUGGGCGCGUUGAAGAACGCCGAUAAGGUGAAUGAGAUUGUCGGUAAACUGCGGGCCUCGGGUUUCAAAGUCUAUACGUCGCCUUCGACGCCGGUACAGGGUAAAAUUACCCGCAUCCUCGUCGGCCCGGAUGCGUCAAAAGACAAGCUGAAAGGCCAGCUGGGCGAUCUGCAGCAGAUCUCCGGGCUUAGCGGGGUGGUGAUGGGCUUCACCCCGAACUGA SEQ ID NO: 71AUGGCACAACGAGAUUAUGUACGCCGCAGCCAACCGGCUUCUUCGCGGCGCAAAAAGAGCACGACCCGAAGCUCAAGGAAUAAGCAAAGCAGCCUUCCGGCGAUUUCACCGGCGAUGGUGGCGAUCGCGGCGGCUGUGCUGGUGGCCUUUAUCGGUGGCCUCUAUUUCAUUACGCAUCAUAAGAAAGAAGAAGCGGAAGCGAUGCAAAAUCGCCAGGCCGCCGGCAACGGCUUGCCGCCCAAACCGGAAGAGCGCUGGCGCUAUAUUAAAGAGCUGGAAAGCCGCCAGCCUGGCGUCCGCGCGCCGACCGAACCGACCGCCGGUGGCGAAGUCAUGAAACCGGAACAGCUGACCGACGAGCAGCGCCAGCUGCUCGCCCAGAUGCAGGCCGAUAUGCGCCAGCAGCCGACCCAGCUGACCGAAGUGCCGUGGAACGAACAAACGCCGGCGCAGCGCCAGCAGACGCUUCAGCGUCAGCGUUUAGCGCAGCAACAGCAGCAGGCGCAGCAGCAACAGUGGGCGCAGACUCAGGCGCAGACCGUCCAACAGCAGCCGCCGCGCGUUCAGCAGCCGAAGCCGGUUCAGCAGCAACAGCCGAAGCAGACCGCGUCAAACCAGCAGCCGUACCAGGAUCUGCUGCAGACGCCAGCGCAUACCAAUACCACGCAGCCGCGUACCCAGGCCGCGGCGCCGGUAACUCGGGUGGAAGAAGCGCCGAAAACCACCGCCGAGAAGAAAGACGAUCGUAGCUGGAUGAUCCAGUGCGGCUCUUUUAAAGGCGCCGAGCAGGCCGAAACCGUCCGCGCUCAGCUGGCUUUCGAAGGGUUUGCUUCGCACAUUACCACUAACAACGGCUGGAACCGCGUGGUUAUUGGCCCGUUGAAAGGCAAAGAAAGCGCCAACGAGAUGAUCACCCGCCUGAAGAUGGCUGGACACGCGAACUGCAUUCGUCUCGCCGCCAGGGGUUGA SEQ ID NO: 72AUGAGCGCGGGAAGCACCAAAUUUACCGUCAGCCGUAUUGCGGCUCUUUCACUGGUUUCACUCUGGCUGGCCGGGUGUACCAACACCAAUAAUCCGCCUGCGCCGGUUAGCUCUGCCGGCGGCGCCGCCUCUUCCAGCACCAACUCCGGCAUGCUGAUUACGCCGCCACCCUCCGGCGUCAAGUCCGCUCCUCAGGCGCAGCCGAUUCAGCCGAUGCAGACCCAGACCAUUCAGCCGGCGCCGGUGGCGCAGGAGCCGGUACAGACGGUAAAUGGCCGGAUCGUUUACAACCGCAAAUAUGGCGAUAUUCCGAAAGGUAGCUAUACCGGCGGCAGUACCUAUACGGUAAAACGCGGCGACACGCUAUUCUAUAUCGCCUGGGUCACCGGCAACGAUUUCCGCGACCUGGCGCAACGUAACAAUAUCCCGGCCCCGUACGCGCUGAACGUGGGGCAGGUACUGCAGGUCGGUAACGCCUCAGGCCAGCCGAUCACCGGCGAAAACGCCGUUUCUCAGGCCAGCGCAAGAGCGAGCGGCGGUGCGACGACCAGCACAACUUCUGCACAAAAAUCGACCGCGGUGGUUGCUUCACAACCGACUAUUACGUAUUCUGAAUCUUCAGGUGAACAGAGUGCUACCAAGAUGUUGCCUAAUAAUAAACCAGCGACCACAACCACAACGGUUGUCGCGCCGGUGACGGCACCAACAACGGUGAGCACAACCCAGCCGACUGCAAGCAGUACGUCAACCAGUUCGCCGAUCUCAGCAUGGCGCUGGCCGACUGAUGGCAAGGUUAUCGAGAACUUUAGCGGCGCGGAAGGCGGCAAUAAAGGCAUCGAUAUUGCAGGCAGUAAGGGACAGGCUAUUGUCGCGACCGCCGAUGGGCGCGUCGUCUAUGCCGGUAACGCACUGCGCGGCUACGGUAAUCUUAUUAUCAUCAAACACAACGAUGAUUACCUGAGUGCCUACGCUCAUAACGAUACCAUGCUGGUUCGGGAGCAACAGGAAGUCAAAGCGGGGCAGAAAAUCGCUACCAUGGGUAGCACCGGAACCAGCUCAACAAGAUUACAUUUUGAAAUUCGUUACAAGGGGAAAUCCGUCAACCCGCUGCAGUACUUACCGCAGCGAUAA SEQ ID NO: 73AUGCGUAAGCAAUGGCUGGGGAUCUGCAUAGCAGCGGGGCUGCUGGCGGCAUGUUCGAGUGAUGACGUGCAACAAAAAACGGUCAGUACUCCACAGCCGGCCGUCUGUAAUGGCCCGACGGUUGAGAUCAGCGGCGCCGAUCCGCAGUAUGAAACGCCGAACGCCACGGCGAAUCAGGAUUAUGAGCGCGACGGUAAAAGCUACAAAAUCGUUCAGGAUCCGGCCAACUUUACUCAGGCCGGUUUCGCGGCGAUCUAUGACGCAGAACCCAACAGCAACCUGACCGCCAGCGGCGAAGCCUUCGAUCCGACUCAGUUGACCGCAGCGCACCCGACGCUGCCGAUCCCGAGCUACGCGCGGAUCACUAACCUUGCCAACGGACGGAUGAUCGUCGUGCGGAUUAACGAUCGCGGUCCCUAUGGCAACGAUCGGGUCAUCUCGCUUUCCCGCGCAUCCGCUGACCGCCUGAACACCUCCAACAACACCAAAGUGCGCAUCGACCCCAUCAUCGUCGCGCCUGACGGUUCGCUUUCCGGCCCGGGGAUGGCCUGUACCACCGUCGCCAAACAGACUUACGCCCUGCCCGCCCGUCCGAAUCUGGACGGUGGGGACGCCGCUGGCAUGAGCCAGCCCGCGCCCACUGACGUUCGCCCGAUCAGCAACAGCACGCUGACGCCGGCAGACAGCGUGGGCGCGCCGGUGAACAGCGGCGGUUUCCUCGGCGCGCCGACGCCCCUGAACAACGGCGUGCUGGAGAGUAGCGAACCAGCGGCAGCCGCCGCGACGGCUCCUGCCGCCGGCGCCACGCCAACAGCGCCAGUGACCGCGCCUGGCUCCAUUCAGGGUAAUGUGGUGCCCGCUGCGGCCACCGCCGCAGCCGCUGGCGCCGUGGCGGCCUCGUCCUCCGCGACCUCCAGCGCCAGCGGUAAUUUUGUUGUCCAGGUGGGCGCAGUAAGCGACCAGACGCGGGCGCAGCAGUAUCAGCAGCGCCUGAGCCAGCAGUUUUCUGUGCCAGGCCGGGUCAUGCAAAACGGCGCGGUCUGGCGUAUUCAGCUGGGUCCCUUUGCUGAUAAAGCACAGGCCAGCGCCGUGCAGCAGCGCCUGCAAAGCGAAGCGCAGCUGCAGUCCUUUAUUACUCGCGCCAACUAA SEQ ID NO: 74AUGGAUGAUUUCAAACCAGAAGACGAUAUGAAAGCCGAUCGCAACGAUCGUCGUGCUGGUCGUUCCCGUCAGUCUUCCGAGCGUGAUGCCGAUCCGCAGAUCAAUUUUGACGAUGUUGAUCUUGAUGCCGAUGAAGGCCGUCCGACGCGCGCUGGUAAGGCCCGUCGCGAGCGUGAAGAGGAAGAGUUCGAAGAAGAACUGGAUGCGCAAGACGAGGAGAUGCUCGAAGAGCAGCCUGUAGAGCGUCGUCCGCGCAAGCGUAAAAAAGCGCCGGCCAAACCGGCCUCCCGCCAGUACAUCAUGAUGGGUGUGGGGAUUCUGGUGCUGCUGCUGUUGAUCGUGGGUAUCGGUUCCGCACUGAAAUCGCCAUCAUCUUCCAGCCAGCAGACCGCUUCCGGCGAGAAGAGCAUUAAUCUGUCUGACGACCAGUCCGCCAGCAUGCCUGCUGCCGGCCAGGACCAGACUGCCGCCGCUAACAGCACCUCACAGCAGGACGUAACGGUACCGCCUAUUGCCGCGAACCCGACGCAGGGCCAGGCAGCGGUUGCGCCGCAGGGCCAGCAGCGUAUCGAAGUUCAGGGCGAUCUGAACAAUGCCUUGACCCAGCAGCAGGGCCAACUGGACGGCGCCGUGGCUAACUCGACGCUGCCGACUGAACCGGCUACCGUCGCGCCAAUCCGGAAUGGCGCCAAUGGCACCGCGGCGCCGCGCCAGGCGACCGAGCGUCAGACAGCAGCGACCCCGCGUCCGGCUGAACGUAAGCAUACCGUUAUCGAAGCGAAGCCGCAGUCGAAGCCACAGGCCGUGGCGAAAACGCCGGUAGAAUCGAAGCCGGUCCAGCCGAAGCAUGUUGAAAGCACGGCGACCACCGCUCCGGCGAAAACGUCCGUCAGCGAAAGCAAACCGGUGGCCACCGCUCAGAGCAAACCGACCACGACGACCGCAGCGCCAGCGGCAACGGCAGCUGCGGCAGCGCCGGCAGCGAAGACCGGGAAGACGGCAGGUGACGUCAGCUCAAUGAAAACUGCGCCGUCGGGUCACUAUACUCUGCAGCUCAGCAGCUCCUCUAACUACGACAACCUCAACAACUGGGCGAAGAAAGAGAAGCUGGAUAAAUAUGUUGUCUAUGAAACGUCGCGUAACGGCCAACCAUGGUACGUGCUGGUGAGCGGUAUCUAUGCAUCGAAAGAUGAAGCGAAACGUGCUGUCACCUCGCUGCCGGCGGACGUGCAGGCGAAAAAUCCAUGGGCAAAACCGCUGCAUCAGGUUCAGGCUGACCUGAAAUAA SEQ ID NO: 75AUGUCAAAGGCAACCGAACAAAACGACAAGCUUAAACGAGCGAUCAUCAUUUCAGUCGCGCUGCACAUCAUUCUGAUCGCGCUGCUGAUCUGGAGUUCGUUUGACGAGCAUCUGGAUGCCUCUGCCGGCGGCGGCGGCGGAUCGUCGAUUGAUGCCGUCAUGGUCGAUCCGGGGGCGGUGGUAAAUAACUAUAACCGUCAGCAACAGCAGCAGGCCAGCGCACGUCGCGCCGCUGAACAGCGUGAAAAACAGGCGCAGCAGCAGGCGGAAGAGUUACGUGAGAAACAGGCGGCGGAACAGGAACGGCUGAAACAGCUCGAACAGGAGCGGCUGCAGGCGCAGGAAGCGGCGAAAGAAGCGAAGGAGCAGCAGAAGCAGGCUGAAGAAGCGGCUGCCAAGGCCGCCGCGGCGGCAAAAGCCAAAGCGGACGCACAGGCAAAAGAAGCGCAGGAAGCCGCUGCCAAAGCGGCCGCCGAGGCGAAAGCGAAGGCGGAUGCCCAGGCGAAAGCGGCAGAACAGGCGGCGGCCAAGGCGGCUGCUGACGCGAAAAAGCAGGCCGAAGCCGCUGCAGCGAAAGCCGCUGCCGAGGCGAAGAAACAGGCGGAAGCUGAAGCGGCGAAAGCUGCGGCCGAGGCGCAGAAGAAAGCGGAAGCGGCGGCUGCGAAGAAAGCGCAACAGGAAGCGGAGAAAAAAGCCCAGCAGGAAGCGGCUAAGCAGGCGGCAGCUGAAAAAGCGGCUGCCGAAAAAGCCGCUGAGAAAGCCGCCGCGCAAAAAGCGGCCGCUGAGAAGGCCGCCGCCGAGAAAGCCGCAGCCGCUGAAAAAGCGGCGGCAGCGAAAGCGGCUGCAGCAGAGAAGGCUGCAGCUGAUAAAGCGGCCAAAGCGGCAGCAGCAAAAGCCGCGGCGGCGAAGAAAGCGGCGGCUGCGAAAGAAGCGGACGGCGUUGACAACCUGCUCGGCGAUCUGAGUUCUGGUAAGAAUGCGCCUAAAACAGGCGGUGGGGCCAAAGGAAACAAUGCCUCCGCUGCCGGGAGUGGUAAUACUAAAAACAGUGCCUCAGGGGCUGAUAUCAACAACUAUGCCGGACAGAUAAAAUCGGCGAUUGAAAGUAAGUUUUAUGACGCAUCGUCCUAUGCGGGCAAAACAUGUACCUUGCGUAUCAAACUUGCUCCUGACGGCCUGUUGUUAAAUAUACAGUCCGAAGGUGGUGAUCCUGCUCUGUGCCAGGCCGCUCUUGCCGCAGCCCGACAGGCUAAGUUUCCGAAACCACCUAGCCAGGCAGUAUAUGAAGUCUUCAAAAAUGCGCCACUGGACUUCAAACCUCAGUGA SEQ ID NO: 76AUGUUUUUUUUAAGUAUUUUUUACAUGGAGAUGACAAAAGUGAAAUUAAGCGCUCUGUUUAUUGCCCUGAUUCCUCUACUGGGCUCGCCGGUUAUUCAUGCAGAAACUACUGCUGCGCCGGUUCUGGAAAAUCGCGCUGCGCAGGGAGAUAUCACCACUCCUGGCGGCGCGCGUCGUUUAACAGGCGAUCAAACCGAAGCGCUGCGCGCCUCGUUAAUCAAUAAGCCAGCUAAAAACGUUAUUUUGCUGAUUGGCGAUGGCAUGGGUGAUUCGGAAAUUACCGCUGCGCGAAACUAUGCCGAGGGGGCGGGCGGUUUCUUUAAAGGAAUUGAUGCUCUGCCGUUAACCGGGCAGUACACGCAUUAUUCGCUGGAUAAAAAAACCGGGAAACCGGACUACGUGACCGACUCGGCGGCCUCCGCCACCGCCUGGACCACCGGCGUGAAGACUUAUAACGGCGCGCUGGGCGUCGAUAUUCAUGAGAAUGCGCAUCAGACCAUCCUCGAGCUGGCGAAAGCGGCGGGGCUGGCCACCGGCAACGUUUCCACCGCCGAGCUGCAGGACGCCACCCCCGCGGCGUUGGUAGCGCAUGUGACAUCGCGUAAAUGCUACGGCCCGACGGUCACCAGCGAAAAAUGCCCCAGCAAUGCGCUGGAAAAAGGGGGCAAAGGCUCCAUUACCGAACAGCUGCUGAACGCCCGACCGGAUGUCACCUUGGGCGGCGGCGCGAAGACCUUUACCGAAACGGCGACGGCGGGCGAGUGGCAGGGCAAAACCCUGCGCGAGCAGGCGCAAGCGCGCGGCUACCAGAUUGUGACCGACGCGGCUUCUCUUGCCGCCGCGACGGAAGCCAGUCAGGAUAAACCGCUGCUGGGACUCUUUGCCGAUGGCAAUAUGCCGGUACGCUGGGAAGGGCCGAAGGCGUCUUAUCACGGUAAUAUCGAUAAGCCGCCGGUGACCUGUACGCCAAACCCGAAGCGUGACGCCUCGGUGCCGACGCUGGCGCAGAUGACGGAGAAAGCGAUUGACCUGCUCAGUCGCAACGAGAAAGGUUUCUUCCUGCAAGUCGAAGGCGCUUCCAUCGAUAAGCAGGACCAUGCGGCGAAUCCGUGCGGCCAGAUCGGCGAAACGGUUGAUCUUGACGAAGCGGUGCAGAAGGCGCUGGAAUUCGCGCGAAAAGACGGUAAUACCCUGGUGAUCGUCACCGCCGACCAUGCGCAUGCCAGCCAGAUCAUCCCGGCGGAUAGCAAAGCCCCGGGGCUGACCCAGGCUCUGAACACGCACGAUGGCGCGGUGAUGGUGAUGAGCUACGGCAACUCUGAGGAAGAGUCGAUGGAGCACACCGGCACCCAACUGCGCAUUGCGGCCUACGGUCCGCAUGCGGCUAACGUCGUAGGCCUGACCGAUCAGACCGACCUGUUCACGACCAUGAAAGCUGCCCUGAGUCUCAAAUAA SEQ ID NO: 77AUGUCACUGCCGUUCAAACCCCAUAUUAUCGCCCUGCUCUGUAGCGCUGGCUUACUCGCGGCGGCAGGAACACUCUAUGUGCAAAGCCGAACCCCAGCGACGAUCGCUGAACCGCCUGCGCAGCAAGCGCCAGCGCCCGCAGCGUCGACGACACAGCCGGUGGCCGCCACUUACACCCAGGCGCAAAUUGAUCAGUGGGUCGCCCCUAUCGCGCUCUACCCGGACAGCCUGCUGUCGCAGGUGUUGAUGGCCUCCACUUAUCCCGACAACGUCCUGCAGGCGGUCCAGUGGUCCCAGGAUAACCCCGCGAUGAAAGGGGAUGCGGCCGUGCAGGCGGUUGCCAGCCAGCCGUGGGACCCUAGCGUCAAAUCUCUUGUCGCUUUCCCUGCCCUGCUGGCGAUGAUGGGCGAGAAUCCGCCCUGGGUGGAAAAUCUUGGCAAUGCGUUUUUGGCCCAGCCGCAUGAUGUGAUGGAUUCAGUGCAGCGCCUGCGCGCCAUUGCCCAACAAACCGGGACGCUGAAAUCCACACCGCAGCAGAAAGUGAUUGUCACCCCUGCCGCACCGGUUUCAGCCAGCAGCAGCACGGCAGCAACCGCAACCGCCCACACAGCGGCGCCUGCGCCCACGCAGGUCAUUAAAAUAGAGCCGACCAAUCCACAGGUGGUCUAUGUUCCCAGCUAUAACCCCUCCACCGUCUAUGGUACCUGGCCGAACAGCGCCUAUCCGCCGGUCUAUCUGCCGCCCCCUCCCGGGGAGCAGUUUACCGAUAGCUUCGUCAAAGGCUUCGGGUACAGCCUCGGCGUGGCCACCACCUGGGCGCUGUUCAGCAGUAUCGACUGGGAUGAUGAUGACCAUCACCAUCACGAUGACGACUACCACCACGGCGAUUACUCGCAUAAUGGCGAUAACAUCAAUAUUAAUGUAAAUAAUUUCAAUCAUAUAACAGGAGAAAACCUGCCGGGAAACCACGUUAACUGGCAGCACAAUCCUGCCUAUCGCGGACACACACCGUAUCCCGAUAAUACGGUAGCUCAGCGCUUCCAUCAGACCAACGUUUCCGGCGGACUGAGCGCGACCCAACAUGCGCCAGUCGAUCGCGAAGCGCAGCGCCAGGCAGCGAUGACCCAGCUGCAGCAUAACGUACCGACGGCCACAGCGGGCAACCUGGCGGCAAACAACGCCUCACGCGACGCCCAGCGUCAGGCGGCCUCGGCGCAGCUGAAGCAAGCCACCCAACGCAGUAAUUACCGCGGUUACGACAGUACGCCGACCCAACAGCAGCGUCGCGAGGCGGCAAAAACGCAGCUGAAAAACCCCACGCCGCAGCAACAGCAGCGUCGAGAAGCCGCCAGGAGCCACGAGCAGAACCGCACACCUCAGCAGCAGCAGCGCCGGCAGCAGUUCCAGUCCGCCACGCCAGCCCAGCGUCAGCAGACGCUCAGCCAUCUGCGCGCCAACGCCCUUAGCGGCAACGAAAGCCGCGCCCCCUCCUGGCAAGCGCAGCAGGAACGAGGACUGCAGAGCCGCCAGUUUUCCGGCGUAAACCGCGAGUUACGCGAUGGCACCAGAGAACGUCUUUCCGAACACCAUGAACUGCGUCGCCGCUAA SEQ ID NO: 78AUGUUUAAGUUUAAGGCUUCUUAUGUCGCACUGGCGGCAGUAUUAACCUCGUCGGUAGUUUAUGCCGACCCCACAAGCUAUACGCACUCUUCCGGCGCCACGGUUAUCGAUAUUGAAAAGCCGAACGCCGCCGGUGUCUCCCAUAACCUGUACCGCGACUUCAACGUCGGCGCCAAUGGCACCAUCCUCAAUAACAGCGGCGAUGAUGUCAGCCACAGCACAUUUGGCAAUAUCGCCCGCAACAAUAAUCUGACCGCCGGCAGCGCUUCGGUGAUUUUGAACGAGGUGACCUCCAAAAACGCCAGUAGCCUGAAGGGCUUUAUCGAAGUCAACGGUCAGAAAGCGGAUGUGGUAAUCGCCAACCCGAACGGCAUCACCUGUUCCGGCUGUAGCUUUGUUAAUACCAACAAGGCUAUCCUGACCACCGGCAAGGUUAAUAUGACCGACGAUGGCGCUAUCGGCAGCUAUACCGUAACGGGCGGCACCCUCACCAUCGGCGAAAAUGGCAUGAACGCCGCCAACGGCUAUGCGGUUCUGCUCGCCGACGCGAUCAAUAUCAACGGUAAAGUGCAGGCCAACAACGCCCUGGUCAGCGCGGGCAACUUCACCAUGGAUAACAGCUCUGGCUCGGUGACCUCCGCUGGUAAAAAGGCCACCCUGAUCCAGAUGACGGUUAACCCGCAGUACAGCAUCGACGUCAGCAGCCUUGGCGGCAUUGAGGCCAACAGCAUCAGCAUGGUCGGCAAUAACAUCGGCUUUGGCGUACGUAAUAAAGGCUCUAUCGUCGCGAAUAGUUCGCUGCAGCUCACCAGCAACGGUAAUCUGCUGAACAAAGGCACGAUCAAAAGCAACGGUCUGCUGAGUCAGGUCGCCACCGCCUCGGGCAUCACCAAUGACGGUAGCAUCGCCGGCGCCUAUUAUUUAAUGCUCUCCAGUGGCGAUUAUAUCGUUAACACCGGUUCUCUCUCCGGCGGCCAGCUGAUUGCCACCGCUAACGGCAACAUCACCAACGGCGACUCAGGCACGAUGACCGGCACCAGUGGAUUAAGCCUGACCAGCGGCGGGAAAAUCCGCAACGAAGAAAAAGCCUCCCUGCUGUCAAAUAACCAGAUUGCCGCCACGGCAAUCGGUGAUUUCCUCAAUGAAGGCAAAAUCAGCGCCAAACACACCAGCCUGACGUUUGUCGGCGACAGCUUUAAAAACACUGGCAAUAUUAACUCUACUGGCCAAACCACCAUUCAGUCGCUUAAACAGGACGGCAGCGCCAAUACGGGCGAGAUCUAUAACCUCGGCAAUAUCACCGGCGAAAAUAUCAAUCUGCAGACCAAUGGCACGCUGGCGCAAAGCAGCAGUGGUCGUAUUGAGGCAACCAACGCCAUUACCGCCCACAGCUACUGGCUGAACCAAAAUGGUUAUAUGAAUGCCGCCGAUAUCACCACCGAUCACGGCGUAGUGAAUAAUUAUGGCAAUAUUACUGCCAAAAAUAUUUCAAUCACGACCUACUCAGAUAUCACCAACGAAGGGCAGAUCAGCAGCACCGGCGACCUGACCUUAAAUACCAAAAAUAAAGGCGCGAUCUACAAUUAUUCAACCCUCAGCGCGGGCGGCAACAUGACGUUAACCGCCACCAAAGUGGUCAAUGGUGGUAAAAGUUGCGGCAUACUGGGCCUGGCGAAAUGCGGCGUCGGGACGUUAACUGCUGACAAGCUGGUACUGAACUCAUCGCAGAAAUAUGUUAGCGACAUGGGUGGAAAACAGUAUUUCAAGAGCACCGAAGUCAACACGGUGAAAUAA SEQ ID NO: 79AUGAUGGACAACCUACGCACGGCCGCCAACAGCGUCGUGCUCAAGAUUAUUUUCGGUAUCAUUAUCGUCUCGUUCAUUUUGACCGGGGUGAGUGGUUACCUGAUUGGCGGUGGCAAAAACUAUGCCGCAAAAGUGAAUGGCCAGGAGAUUGGCCGUGGGCAGUUUGAAAACGCCGUCGCCAGCGAACGUAACCGUAUGCAGCAGCAGCUUGGCGAUCAAUUCUCCGAGCUGGCGGCGAACGAAAACUACAUGAAAACCAUGCGCCAGCAGGUGCUGAACCGCCUGAUCGAUGAGUCGCUUCUGGAUCAGUAUGCCCGCGAGCUGGGCCUCAGCAUCAGCGAUGAGCAGGUGAAGCAGGCGAUCUUCCAGACCCAGGCGUUCCAGACGAACGGUAAGUUCGACAACCAGCGUUUCAGUGGUAUUGUCGCCCAGAUGGGGAUGACCACCGAUCAGUACGCCCAGGCGCUGCGUAACCAGCUGACCACGCAGCAGCUGAUUAACGCCAUUGCGGGUACCGACUUCAUGCUGCCGGGCGAGUCCGAUCAGCUGGCGGCGCUGGUAUCUCAACAGCGGGUGGUCCGCGAAGCGACCAUCAACGUAAAUGCCCUGGCGGCAAAACAGACCGCCAGCGAUGAGGAAAUCAACGCCUUCUGGCAGCAGAAUCAGGCCCGUUUUAUGGCGCCGGAGCAGUUCCGCGUCAGCUACAUCAAAAUGGAUGCCGCCAGCAUGCAGGAGAGCGCCUCUGACGAAGAGAUUCAGUCAUGGUACGACCAGCACAAGGAUCAGUUCACUCAGCCGCAGCGCAACCGCUACAGCGUGAUUCAGACCAAAACUGAAGCCGAUGCGAAAGCGGUACUGGCCGAGCUGCAAAAAGGAGCGGACUUCGCCACGCUGGCGAAAGAAAAAUCGACCGAUAUUAUCUCUGCCCGCAACGGUGGCGAUAUGGGGUGGAUGGAAGAUGCCUCUACCGUGCCUGAGCUGAAAGAUGCCGGGCUGAAAGAGAAAGGCCAGCUGUCUGGCGUGAUCAAAUCCUCGGUUGGCUUCCUGGUAGCUCGUCUGGACGACGUCCAGCCGGCGCAGGUGAAGCCGCUGGCUGACGUGCGUAAUGACAUUGCGGCGAAAGUGAAGCAGGAAAAAGCGUUGGAUGCUUACUACGCGCUGCAGCAGAAGGUGAGCGAUGCGGCCAGCAACGAUAAUGAAUCGCUGGCGAGCGCAGCGCAGGUCGCCGGGCUGAAGGUCGUAGAAACCGGCUGGUUUGGCCGCGAUAACCUGCCGGAGGAGCUGAACUUUAAACCGGUCGCUGACGCUAUUUUCAACGGCGGUCUGGUGGGUGAGAACGGCGCGCCGGGCAGCAACUCCGAUAUCAUUACCGUUGACGGCGAUCGCGCUUUUGUUCUGCGCAUUAGCGAACACAAAGCCGAGGCGGUGAAGCCGCUGGCCGAAGUGAAGGCACAGGUUAGCGAUAUCGUUAAGCACAAUAAAGCGGAACAGCAGGCGAAACUGGAGGCCGACAAGCUGCUGGCGGCGCUGAAAGACGGCAAAGGCGAUGAAGCGAUGAAGGCGGCUGGCCUGAGCUUUGGCGCGCCGCAGACGCUUUCUCGUACCGGCCAGGAUCCGCUGAGCCAGCUGGCAUUUACCCUGCCGCUGCCGCAGCAGGGUAAACCGGUCUACGGCGUGGGCAGCAAUAUGCAAGGCGAUGUGGUGCUGGUAGCGCUGGAUGAGGUGAAAGCCGGCAGCAUGCCGGAAGAGCAGAAGAAGGCCAUGGUUCAGGGGAUCACCCAGAACAAUGCCCAAAUCGCUUUCGAAGCGCUGAUGAGCAACCUGCGCAAGGCGGCGAAAAUUAAGCUCGGCGACAGCAUCGACCAGCAGCAGUAA SEQ ID NO: 80AUGUUCAGGUUAAACCCUUUUAUCCGGGCGGGAUUGUCUGCGUCCGUCGUAUCGUUGGCGUUUCCGGCUCUGGCCGAUGUGAAUGAAGAAACGCUGGUGGUGACCGCCUCGGCCACUGAACAGAAUGUCAAAGACGCGCCGGCGAGCAUCAGCGUCAUCACCCAACAGGAUUUACAACGCAAGCCUGUUCAGAACCUGAAAGACGUGCUGCGCGAUGUGCCUGGGGUCCAGCUCACCAACGAAGGGGAUAACCGCAAGGGCGUUAGCAUCCGCGGUCUGAGCAGCAGCUAUACCCUGAUCCUGGUCGACGGCAAGCGCGUUAACUCGCGGAACGCCGUCUUCCGCCACAAUGACUUCGACCUUAACUGGAUCCCGGUGGAUGCUAUUGAGCGUAUCGAAGUGGUGCGCGGCCCGAUGUCCUCCCUCUACGGCUCCGAUGCGCUCGGUGGGGUGGUCAACAUUAUUACCAAAAAAAUCGGCCAGAAAUGGACCGGGACGCUGAGUGCUGAUACCACUAUUCAGGAGCACCGCGAUCGCGGGGAUACCUGGAACGGCCAGUUCUUCACCAGCGGCCCGCUGAUCGACGGCGUACUUGGAAUGAAGGCCUACGGCAGCCUGGCAAAACGCGCCAAGGACGAUCCGCAGUCAUCCAGUAAUGCCACCGGCGAGACGCCGCGCAUCGAGGGCUUCACCAGCCGCGAUGGCAAUGUUGAAUUCGCCUGGACGCCGAACGAAAACCACGAUUUUACCGCAGGCUACGGCUUUGACCGUCAGGAUCGCGAUUCCGAUUCCCUUGACCGCAACCGCCUUGAGCGGGAGAACUACUCUCUGAGCCAUAACGGCCGCUGGGAUAUCGGCAAUAGCGAGCUCAAGUUCUACGGCGAAAAGGUGGAUAACAAAAAUCCAGGGCAGAGCGGGACUAUUACCUCGGAAAGCAAUGCCAUCGACGGCAAGUAUGUCCUGCCGCUGGGCAUGAUUAACCAGCUGGUGACCUUCGGCGGCGAAUGGCGCCACGACAAACUUAAAGAUCCGGUCAACCUGAGCAGCGGCGGCCAGUCAACGUCGGCCAGCCAGUACGCCCUGUUUAUCGAAGACGAAUGGCGCAUCAUCGAGCCGCUGGCGCUGACCACCGGCAUUCGUAUGGACGACCAUCAGACCUAUGGCGAUCACUGGAGCCCGCGCGCCUAUCUGGUGUAUAACGCCACCGAUACCGUCACCGUCAAAGGCGGCUGGGCGACGGCGUUUAAAGCCCCGUCGCUGCUGCAGCUUAACCCCGACUGGACCACCAACUCCUGCCGCGGCUCGUGCAGCAUCGUCGGUAACCCGGAUCUGAAACCGGAAACCAGCGAAAGCUUCGAGCUCGGUCUCUACUACCGCGGGGAAGAGGGCUGGCUUGAAAAUGUCGAAGGCAGCAUCACCACCUUCCAGAAUAAUGUCGACGACAUGAUCGACGUUCUGCGCACCUCCAGCGCCAGCGAAGCGCCGGGCUACCCGAACUUUGUCGGCUGGAAAACUGUCAACGGCAAGCGCGUGCCGAUCUUCCGCUAUUUCAACGUCAACAAAGCCCGCAUCAAAGGGGUGGAGACGGAGGUGAAGAUCCCGUUUGGCGAUGAGUGGAAGCUGACGGUGAACUACACCUACAACGAUGGUCGCGAUCUGAGCAAUGGCGGCGACAAACCGCUGCAGACGCUGCCGUUCCAUACCGCCAACGGCACGCUCGACUGGAAACCGCUGGACGACUGGUCCUUCUACGUGACGGCCAACUAUACCGGCCAGCAGCGCGCGGUGAGCGCCACCGGCAAAACGCCGGGCGGCUACACCCUGUUUGACGUUGGCGCGGCAUGGCAGGUGACCAAAAACGUGAAACUGCGCUCCGGGGUGCAGAACGUGGGUGAUAAAGAUCUGAGCCGGGACGACUACAGCUAUACCGAAGAAGGCCGUCGCUACUUUAUGGCGGUGGAUUAUCGCUUCUGA SEQ ID NO: 81AUGAACAGAGCCGCCACGCUGACCCUCAACGCGCCCCUGCUGAUGCUCGUCGCUGCGCUGGCGCUUUCAACCCCUUUCACCGCCGGCGCCGCGCCGGCCUUUCUUGAUUACGCCCAACAGCAAACCCAGCAAUCUCAGGCGCAAGAAAAAAACGAUGCCGCAAGCGCAAAACAAACACAAGAAAGCCGCCAGAGCGCAGAUAAUAAAAAAACCGGUACCAGCACCUCACAAUUACAAAAAAGAAUCACCAGCCAGCAGGCGGCGAUUGCACAAAAAGAUAAGCUUAUACAGCAAUUAAAAAAACAGCUUGCCGCUACGCCGCAAACGGAUACUGCCGGAGCGAAUGAGCAAGCGGCGUUGAAUAAGAGAAUUAAUGAAUUACAGGUCGCCUUAAGCGCCGCUACUGCAGAAAAAGAGGCAUUAAUAAAAAAAGCAGGCGUUGUGCAGAAUAAUAAUCUACAGCAAAGCCAGGCCGCGGCGCGUCAGCAGAUCCAGCAAUUAACGACGCAGAUUCAGCAAGCCGAAGCUGAAAAUAAACGCCUCAGCGCCAGCUUUACCACGCUUAAUAAAGAUAAACACGCGCUAAUGACCCAACUGGCCGCAACGGAAAAAGAGAAACAGGCCGCUCUUGAGCAGGUCAAAGCGCUUAACGCUGACAAACAGCCGCUGACGACCCGGCUGGCCGCCGCGGAAAAAGAGAAACAGGCCGUCCUCGAGCAGGUUAAGGCCCUUAACGCCGAUAAACAGUCGCUGACUAUUCGCCUCGCCGCUGCGGAGAAAGCGCAGCAGGCCGCUGUUGACCAGGCUAAAGCGCUUAACGCUGACAAACAGCCGCUGGCUACCCGACUGGCCGCCGCGGAAAAAGAGAAACAGGCCGUCCUCGAGCAGGUUAAGGCCCUUAGCGCCGAUAAGCAGUCGCUGACUAUUCGCCUCGCCGCUGCGGAGAAGGCGCAGCAGGCCGCUCUUGACCAGGCUAAAGCGCUUAACGCUGACAAACAGCCGCUGGCGACCCGGCUGGCCGCCGCGGAAAAAGAGAAACAGGCCGUCCUCGAGCAGGUUAAAGCCCUUAACGCCGAUAAGCAGUCGCUGACUAUUCGCCUCGCCGCUGCGGAAAAGACGCAGCAGGCUGCCCUCGAUCAGGUCAAAGCCCUUAACGCCGAUAAACAAUCGCUGUCCACCCGGCUGGCCGCCGCGGAUAAAGCGCCGCAUGGCCCCGCUAACGACGCCGCUGCGCCAAAAAAUGAGCCACCAGAGAUGGCGGCCAUAGUGGCAGCCUAUCGCCUGCAGGCGGAUAAAGACAACGCCCAGCUACGGAUGAAAGAAGAUGAAAUCGAACUGCUGAGAACGCAGCUUUCUGUACAGUCCAAAACGCGCAGCGGCGAGAGCGCCGCCGCCAAACUCAGCGCAUCGGGAGAACAGCAGGCUUAUGCGAUCGGCGCCUCGAUGGGAAGCGAGGCGCUCAACGUCCUUACCACCCGUCGUACUCAGGGAGUUACCGUCGACGCAGGCCUGGUGCUGCAGGGCAUCGAAGAUGCCUUUCGCGGCCAGCUUCGUCUCGGAGAGCAGGAACGUAACAAGGCGCUGUUUGAUGUGUCGCAGCAGGUUUUUCAGAACCUGAAUAAAAUAGAGCAGAAAAACAUCAGUGCCGGCAAGAAAUAUCAGCAGGCGUUUGCGCGCAAAAAAGAUGUGGUCUUUAAAGAGGGCGUCUACAGCCGCGUCGAUUACCUGGGUAAAGGAAAAAUAAGCGGUAAUGACCUGGUUACCGUGGUGAUCAAAGAGAUGCUGACGGACGGGACGGUGAUCAACGAUAUGGAAGCGAAAGAUCAGGCGCUUACGCAAAAGCUGGAUGCCUAUCCCCCGGUGUUUCGCGAACCGCUGAAGCGUCUACAGAACCACGGCUCCGUGACGCUCGUCGUCCCGCCUGAAAAGGCCUAUGGCAGUAAAGGAUUACCGCCAAAAAUCCCGCCAGGCGCCACCAUGGUUUAUUCCGUGCGGAUAGUAGAUAGCCAACCCGAGCCGGCAAA AUAGSEQ ID NO: 82AUGAAAAUCCUGUCCGUGCGUCACGCCGCCCUCCCGGCCCUGCUCUUGCCGCUCAUUGCGGCAGCCCAGGCCGCUGAUGAACAAACCAUGGUGGUGACCGCCGCGCCAACCACGGUUUCUGAACUGGAUACCCCCGCCGCCGUCAGCGUGGUGAAUGGGGAUGAGAUGCGCCAGGCCGCGCCGCGCGUCAAUCUCUCUGAAUCGCUGGGCGCCGUGCCGGGCCUGCAGGUGCAGAACCGGCAAAACUAUGCCCAGGAUCUGCAGCUGUCGAUUCGCGGCUUUGGCUCGCGCUCAACCUAUGGCGUGCGCGGACUGCGCAUCUAUGUGGAUGGCAUUCCGGCCACCAUGCCCGACGGCCAGGGGCAGACCUCAAAUAUUGAUAUCGGCAGCGUUGACACCAUUGAGGUGCUGCGCGGCCCCUUCUCUGCCCUGUACGGUAACUCGUCCGGCGGGGUGAUCAACGUCACCAGCCAGACCGGCACCCAGCCGCCCACCGUGGAAGCCAGCAGCUACUAUGGCAGCUUCGGCACCUGGCACUACGGGAUGAAAGCCACUGGCGCCGUUGGCGACGGCAGCCACGCAGGCGAUGUGGAUUACACGGUCUCAACCAAUCGCUUCACCACCCAUGGCUAUCGCGAUCACAGCGGCGCGCGCAAAAAUCUGGCGAACGCCCGGCUGGGGGUGCGCAUCAACGACGUCAGUAAGCUGACUCUGCUGCUGAAUAGCGUGGAUAUCAAAGCCAAUGACGCCGGUGGCCUGACCGCCGAUGAAUGGCGCGAUAACCCGCGCCAGUCGCCGCGCGGCGACCAGUAUAAUACCCGCAAGAAUACCCGACAGACCCAGGCCGGCCUGCGCUAUGAGCGCCAGCUCAGUGCCCAGGACGAUCUCAGCGUUAUGAUGUACGCUGGAGAACGUGAAACCACUCAGUUCCAGUCGAUCCCGCGCGCGCCGCAGCUGAAGCCGAGCCAUGCCGGCGGGGUGAUCGACCUUACCCGUCACUACCAGGGGAUCGAUACCCGGCUGACCCAUCGCGGAGAGCUGCUGGUGCCCGUCACGCUCACCGCCGGUCUCGACUACGAAAACAUGAGCGAGCGGCGCAAAGGGUAUGAAAACUUUGUGAUGGUCAACGGCGCGCCGCAGUAUGGCGAACAGGGCGCGCUGCGCCGUAACGAACGCAACCUGAUGUGGAACGUCGACCCCUACCUGCAGACCCAGUGGCAGCUCACUGACAAACUCUCGCUCGAUGCCGGGGUUCGCUACAGCUCGGUAUGGUUCGACUCGAACGACUACUACAUCACCCCAGGCAAUGGCGAUGACAGCGGUGAUGCCAGCUAUCACAAAUGGCUGCCCGCGGGCUCGCUGAAAUAUGCCCUGACCGACGCGUGGAACGUCUAUCUUUCCGCCGGCCGCGGCUUCGAGACGCCAACCAUUAACGAACUCUCCUACCGCUCCGAUAACCAGAGCGGCCUCAACUUCGGCCUGAAACCCUCCACCAACGACACGGUGGAGAUCGGCAGCAAGACGCGGAUCGGCAAUGGGCUGUUCACCGCCGCCCUGUUCCAGACCAAUACCGAUAAUGAGAUUGUGGUCGACAGCAGCAGCGGCGGGCGCACCAGUUAUAAAAACGCCGGCAAGACCCGCCGUCAGGGGAUGGAGCUGGGGCUGGAUCAGCAGUUUGGCGAGAGCUGGCGUCUGAAGGCGGCCUGGACCUGGCUGGACGCGACCUAUCGCACUAACGUCUGCGACGACGCCAGCUGCAAUGGCAAUCGCAUUCCGGGGAUCGCGCGCAAUAUGGGCUACGCCUCCUUUGGCUAUCAGCCGGAGCAAGGUUGGUACGCCGGGAGCGAUAUUCGCUAUAUGAGCGAUAUCAUGGCCAAUGACGAAAACACCGCCAAAGCGCCCUCCUGGACGGUGGUUGGCCUGACGACUGGCUAUAAAUGGAGCUACGGCAGGAUGGAUAUGGAUCUGUUCGGUCGCAUCGACAACCUGUUCGACCGGGAGUACGUCGGGUCUGUCAUCGUUAACGAGUCUAACGGACGUUACUACGAGCCUGCCCCGGGACGUAACUACGGCAUCGGCCUGAACCUCGCCUGGCGCUUCGAAUAA SEQ ID NO: 83AUGAAAUACACGUCUCACUUCCCGCUGGGGAUCGUCAUUCCUCUGCUCGCCUGUAGCGUGCCGCUGCAGGCGGCAGAGAACAUGACCGAACAAUCGACGCCUGACGAGAGCGCCGCCACUGCCGAAAAUCACGAGGAGACGAUGGUCAUAACCGCCGCCAGGCAGAACCUGCAGGCGCCGGGCGUGUCGACCAUCACCGCAGAAGAGAUCCGCAAACAUCCCCCCGCCCGCGAUGUGUCGGAGUUAAUUCGUACGCAGCCCGGGGUAAACCUGACCGGCAACUCCACCAGCGGGCAGCGCGGCAACAACCGGCAAAUUGAUAUCCGUGGCAUGGGGCCCGAGAAUACGCUGGUGCUGGUCGAUGGUAAACCGGUGACCAGCCGUAACUCGGUGCGGUAUGGCUGGCGCGGCGAUCGUGACUCCCGCGGCGAUACCAGUUGGGUGCCAGCGGAGAUGAUCGAUCAUAUCGAUGUGAUCCGCGGCCCGGCGGCGGCGCGCUAUGGUAAUGGCGCGAUGGGCGGGGUCGUCAACAUCGUGACCAAACCGACCACGCGAGAAUGGCACGGGUCGUGGAAUACCUAUAUGAAUGCUCCGCAGCACCGUAAAGAAGGGGCGACGAAACGUACUAACUUUAGCCUCAAUGGUCCGCUGUCGGACAGUGUCAGCUUCAAUCUCUGGGGUAAUCUGAGUAAAACCCAGGCCGAUGCACAGGAUAUUAACGCCGGGCAUGAAGCGGAACGUACCGGUUCCUACGCCGGUUCUUAUCCCGCCGGACGUGAAGGGGUGGUGAACAAAGAUAUUCACAGUAAGCUGCGCUGGGAGUUUGCCCCGAUGCAGGCCCUGGAGUUUGAGGCCGGUUACAGCCGCCAGGGUAAUCUCUAUGCCGGCGACACACAAAACACCAAUACCAGUACGCUGGUGAAGAGUAUGUACGGGAAAGAGACCAACCGUCUCUACCGGCAAACUUACGGCGUAACAUGGACCGGCGGCUGGGAUAAUGGCGUGACCAGCAACAGCUAUGCCCAGUACGAACACACCCGUAACUCGCGAAUGGAUGAAGGGCUGGCGGGCGGUACGGAAGGGAUCUUCUCCAGUAGCGAGUUUUCAGAUAUCGAUCUGGCCGAUGUCCUGCUACAUAGUGAAGUGAAUAUUCCGUUUACGCUGGGGGUCGAUCAGAAUCUGACGCUGGGGGCAGAAUGGAAUCAGCAGCGGAUGAAAGAUGGCGUAUCGACAACCCAGGCGCUCUCUUAUGGCACUAUCGAUGGCGUAUCGGCUACCGGUCGUAGCCCGUACUCCAGUGCCGAGAUCUUCUCGCUGUUUACCGAAGAUAAUAUGGCGCUAACGGACAGCACCAUGCUGACACCCGCUCUGCGCUUCGAUCACCACAGCAUCGUCGGCAAUAACUGGAGCCCCUCACUGAACCUGUCUCAGGAGCUGACGGACGACUGGACGCUGAAGCUGGGCAUUGCCCGUGCUUACAAGGCGCCUAACCUCUACCAGUUGAACCCGAACUAUAUUCUCUACAGCAACGGUCAAGGCUGUUACGCCAGUAGUUCCGCCUGCUAUCUGAUGGGGAAUAGCGAUCUGAAAGCGGAGACCAGCGUUAAUAAAGAGAUUGGUCUUGAGUACAAGCAUGAUGGCUAUCAGGCGGGGAUCACCUGGUUCCGUAACGACUAUCACAAUAAGAUUGAGUCAGGGUAUGCGGCGGUGGGUACCGCCAGCAACGGCACCACCAAUAUCUAUCAGUGGGAAAACGUACCAAAGGCGUUAGUGGAAGGCCUGGAAGGAACGCUGAAUCUGCCGGUGGGGGAGGCGGUUAACUGGAGCAAUAACCUGACCUGGAUGCUGCAGAGCAAGAAUAAGACGACCGGCGACCGGCUGUCAGUGAUCCCGCAGUUUACCCUGAACUCGACUUUGAGCUGGCAGGUUCGUGAAGAUCUCUCCCUGCAGAGCACCUUUACCUGGUAUGGCCGACAGAAACCAAAACGCUUCAAUUAUAAGGGCGAGGCGGUCAGCGGCAGCGAACUAAACGAAGUCAGCCCAUACAGCAUUGUCGGCCUCAGUGCGACCUGGGAUGUGAACAAAAAUCUGAGCUUCACCAGCGGGAUAGAUAACCUGUUUGAUAUUCGCCACUACCGGGCAGGGAAUGCGCAAACGACCGGCAACGCGACGACGGGAGCUUAUCUGUAUGGCGCGGGUGCCGAGACCUAUAACGAAUCGGGGCGGACCUUCUUUAUGAGCGUUAAUACUCAUUUCUGA SEQ ID NO: 84AUGGAAAAAAACGCUUCUCUGCCUUUCGGCAGUUUCAACUCAUUGGCAUUGUUUACAGGUCUGUGUCUGGGAGCCUCGCCGGCAGCAGGCAUCGCAGCGGAAAAUUCGGUCAAAAAUAGUGAAGAGACGCUGGUAGUGGAAGCCGCUCCGCCUUCACUCUACUCCCCCGGCGCUUCCGCCGAUCCCAAGUUCAAUAAACCGCUGGUCGAUACCACCCGCACCAUCACCGUGAUCCCGGAACAGGUGAUUAAAGAUCAGGGCGUCACCAACCUGACUGACGCCCUCAAAAACGUUCCCGGCGUCGGGGCGUUUUAUGCCGGGGAGAAUGGCAGCUCAACCACCGGGGAUGCCAUCUUUAUGCGCGGCGUGGAUACCUCUAACAGCAUCUAUGUGGACGGCAUUCGCGACAUCGGUAGCGUGACGCGCGAUACCUUCAAUACCCAGCAGGUGGAAGUCAUCAAAGGGCCCGCCGGCACGGACUAUGGCCGCAGCGCGCCCUCCGGCUCGAUCAAUAUGAUCAGCAAGCAGCCGCGCCUUGACUCCGGGAUCGACGGCUCGGCCAGCAUCGGCAGCGCCUGGUCGCGCCGGGGCACUCUCGACCUGAACCAGGCGUUUAGCGACAACGCUGCGUUCCGUCUGAACCUGAUGGGGGAAAAAACGCAUGACGCUGGUCGGGACCGCAUUGAAAACGAACGCUAUGGCAUCGCACCGUCGCUGGCCUUCGGCCUUGAUACCCCAACUCGUCUGUAUCUGAACUAUCUGCACGUCCGGCAGAACAACACCCCGGAUGGCGGGAUCCCUACCGUCGGCCUGCCGGGCUAUUCGGCGCCUUCGCCGAAGUAUGCCGCACUCAACUCCGCCGGGAAGGUCGAUACCAGCAAUUUCUAUGGCACCGACUCCGAUUACGAUAAAUCUACUACCGACAGCGGUACCCUGCGCUUCGAACACGAUCUGACGGAGAAUACCACCGUGCGCAAUACCACCCGCUGGUCGCGAGUGAAACAGGAGUAUCUUUUGACCGCGGUGAUGGGCGGCGCGAACAAUAUCACCGCCCCCGAUAUCAAUGACGUCAACACCUGGAGCUGGUCGCGUCUGGUUAAUACCAAAGAUGUCAGCAACCGUAUUCUGACCAACCAGACCAAUAUCACCUCGACUUUCAAUACUGGCUCGAUAGGCCAUGACGUCAGCGCCGGCGUGGAGUUUACCCGGGAAAACCAGACCAACUAUGGCGUUAACGCCAGGACCGCGCCGGCGGUGAAUCUCUACCAUCCGGUGAGCAACCUGUCGAUUGGCGGGCUGGACAGAAACGGGGCGAACGCCAACGGCCAGACCGAUACCUUCGGGAUUUAUGCCUUUGAUACGCUGACGCUGACCGAGCGGAUUGAGAUCAACGGCGGGCUGCGUCUCGACAAUUACCAUACCAAAUAUGACAGCGCCACCGCCUGCGGCGGCAGCGGACGCGGGGCUAUCGCCUGCCCGCCCGGACAGUCGACCGGCAGCCCGGUCACCACUGUCGAUACCGCUAAAUCCGGCAAUCUGGUUAACUGGAAAGCCGGGGCGCUGUACCGCUUAACCGAGCAGGGCAAUGUCUACGUCAACUACGCCAUCUCACAGCAGCCGCCGGGAGGCAGCAGCUUCGCCCUGGCCGCCAGCGGCAGCGGCAACAGCGCUAACCGGACCGACUUUAAGCCACAGAAGGCGAAAUCCAGCGAGCUGGGCACCAAGUGGCAAAUCUUCGACAACCGUCUGCUGCUCAGCGCGGCGUUAUUCCGCACCGAUAUUGAAAACGAAGUGGCCGCCAACGAUGACGGAACCUGGUCGCAGUACGGCAAAAAGCGCGUGGAGGGGUAUGAACUCUCCGCGACCGGAAACCUGACCCCGGACUGGACGAUUAUCGCCGGCUACACUCAGCAGCAUGCGACAGUGACGGAGGGACAGAACGUUGCACAGGAUGGAUCUUCCGCCCUGGCCUACACCCCGAAACAUGCCUUUACGCUGUGGACGCAGUAUCAGGCCACCAGCGAUCUGUCCGUCGGCGGCGGUGUGCGCUAUGUCGGAAGCCUGCGCCGGGGCAGCGAUGGUGCAGUCGGUACCCCGGAUCACACCGAGGGCUACUGGGUUGCCGACGCCAAACUGGGCUAUCGGGUCAACAGCAACCUCGAUCUGCAGCUCAAUAUGUAUAACCUGUUUGAUACCGAUUACGUGGCCUCCAUCAACAAGAGCGGCUAUCGCUAUCAUCCGGGCGAACCCCGGACCUUUAUGCUGACGGCGAACGUCCAUUU CUGASEQ ID NO: 85AUGGCGACUAUGUACAAAUCGACUCCGUCAGCAGCAUGGUGUAAAAAACGCCUGCUGGUGACCUCUUUGUUUGCAGCAAUUUAUCAGACUUCUGCCAUCGCAGCAGAUACUUCCGCCGUUAGCGGCGAGGCGGUGGAUGACACCUCGGAACAAAUGACCGUCACCGCCCCCGCGCCGGUGCAGAAAGCCGGUAGCGAACACAGCAUCAGCGCCCGGGAGCUGGAGAAUAAAGGCGCUAACGAUUUCGGCUCAAUCAUGCGCUAUGAGCCGCUCAUCAGCGCCACCGGGGCCAGCGGCGGCUCCGGCAACGGCAAAAGCGGCUUCGACCGCGGAGGUUACACCGGCUACAACAUUCGCGGUAUGGAGAGCAACCGCGUAGGCAUCGACGUGGACGGUAUCGCGCAACCCAACGCCACCGGCCGCGGCUACGUCGGCCGCGCCGGGCUCAACACCUUCGGCAUCGGCCGCGAUUAUAUCGACCCGUAUAUGUACGGCAGCGUUGAUAUCCAGUCCGGCGCCACCUCGACGGAAACGGCCAACAGCGCUAUCGGGGGGAAUGUCUCCUUCCGCCCGAAAUCAGCGGAUGAUUACCUGCGCCCGGGCAAGACCAGCGCCUUCGGCUACCGCAGCGGUUACGACUCUGCGGAUCGCAGCUGGCACAACGGGGUGACCGUCGCCGGCGGCGAUGAGUUCCUGCGCGGGAUUUUGGUCUAUAGCCGCCGUGACGGCCAGGAAACUGAAAACAACAGCGGCACCGUCGACGCCUACCCGGCGAACUGGCACUCCGAUGCUUUUCUGGCCUCCGGGAUCUGGCAGCCUAACGAUGAGCACAAGCUGACCAGCACCUUCGACUAUUACCAUAAAACCAACCACACCCACUACGAUACCUGGGACUCCAGCGGCAACAGCACCAUCGGCACCGCCAACCAGACCAGCCAGACCCGGCGCUGGGGCCUGAGCCUGAAGGAUGACUGGACGCCGAUGAACGACUACCUCGACAGCGUCUCCACAAAAAUCUACUACCAGCAUACCGAAGCCCAUGACUGGACUUAUAUGCCGGACAGCGUCACCCGCAAAAUGCAGACGGUGAACUCUAACUACGAUACCGACACCUGGGGCCUGCAGACCGCGCUGGCGAAAACCCUGGGCCGCCACGAUCUGAGCGCCGGUUUCAACGCCAGCACCAGCAAAACCCAGCGGCCGUUCAGCCAGUCGCCGAUCCCCAGCGUUUACAGCGAGAUCAUGCAGCCGGAGGCAGACAGCCGCAGCUACACCCUCGGCGGCUUUGUCCAGGAUAAGAUCAACUUCGAUCUCGACAGCCACAACUUCGCCGUUAUUCCCGGCGUGCGCGUGGUGCAUCAAUCGACUAAGCCGGAAAAUCUGUCCGAUCUCGCCGCCAACAGCAGCGUGCUGAGCGAAUCGUCGGUGGCGAAUCUGUACGGCAAAAACAGCGAUACCCAGGUUCUGCCGUCGUUGACCUUCCAGUACGACCUCACCCCGCGCCUGAUGACCUACCUGCAGUACCAGCGCGGGGCGCAGUUCCCCAACGCCAGCCAGCUGUAUGGCUCCUGGAACCUCGGCUCCAGCUACGCCGGCAGCCAGCAGUAUGCCCUGAUCGGCAAUACCGAUCUGAAGACGGAAACCAGCGAUAAUCUCGAGUGGGGGCUGAAAGGGGAAGUUACCGAAGGCAUCACCCUGCGCACGGCGCUGUUCUACAACAGCUAUAAGAACUUUAUCGCCUAUACCCGCUAUACCCGCGCCAACAAUCCGGGCCAGUUCACGAAUGUGCCGUCGAACAUCUACACCAUUUAUCAGGCGGAAAACCGCGAUAAAGCCUAUAUCUACGGCGGUGAGAUUAGCACCAAAUUUAACUUUGGCACCUGGUUUGAGCAGGUGGACGGCCUGAGCGCCACCCUCGCCCUCGGCUAUAGCGAAGGGAAAUCGAAAUCCAGCUACAGCGGCGAUAAAUACGUCGACCUCGACAGCGUGGCGCCAAUGAAAGCCAUCGUCGGCGUGGCGUGGGACGAUCCGGCGAAACGCUACGGCACCGCCCUGACGGCGACCUUUGUCAAAGGGAAACAGGCGACCGCCACCAACCGCGAAAGCUACAGCAACAGCGGAUCCGCCAUCACCGAUGCCAGCAGCGACUAUAUGCGCGUGCCGGGCUACGGCAUGCUGGACUGGACCGCGUACUGGCAGGUGGCGAAAAACGUGCGCCUCAAUGGCGGGGUCUACAACCUCACCGAUCGUAAAUACUGGGAUUACCUGAGCAGCCGCAAUAUCGAGACCGGCACCAACCAGGACGCCAACGAUAAAGCGCUGGCGGUGAUGCCGGGCCGCACCUGGCAGCUGGGCGUCAACGUCGACUUCUGA SEQ ID NO: 86AUGGCGAUGAAAAAGUUGCUCAUAGCGUCGCUGCUGUUUAGCAGCGCGACUGUAUACGGUGCUGAAGGGUUCGUGGUGAAGGACAUUCAUUUCGAAGGCUUGCAGCGUGUCGCUGUUGGUGCGGCCCUCCUCAGUAUGCCAGUGCGUCCUGGCGAUACGGUGACCGACGAUGAUAUCAGUAACACUAUUCGCGCGCUGUUUGCCACUGGCAACUUCGAGGACGUCCGCGUCCUGCGCGAUGGUGAUACCCUGCUGGUUCAGGUGAAAGAGCGUCCGACGAUCGCCAGCAUCACUUUCUCCGGCAACAAGUCGGUGAAAGAUGACAUGCUCAAGCAGAACCUUGAGGCCUCAGGCGUUCGGGUGGGCGAGUCGCUUGACCGCACGACCAUCGCGGAUAUCGAGAAGGGUCUUGAAGACUUCUACUACAGCGUCGGUAAAUACAGCGCCAGCGUCAAAGCAGUCGUUACGCCGCUGCCGCGUAACCGUGUCGAUUUGAAGCUGGUCUUCCAGGAAGGCGUCUCCGCAAAAAUUCAACAGAUCAACAUCGUCGGCAACCAUGCGUUUUCGACCGAUGAGCUGAUCUCCCACUUCCAGCUGCGCGAUGAGGUGCCGUGGUGGAACGUGGUCGGCGACCGUAAAUACCAGAAGCAGAAGCUAGCGGGCGACCUUGAAACCCUGCGCAGCUACUACCUGGAUCGCGGCUAUGCCCGUUUCAACAUCGAUUCUACCCAGGUCAGCCUGACGCCGGAUAAGAAAGGGAUCUACAUCACCGUCAACAUCACCGAAGGCGAUCAGUACAAGUUUUCCGGAGUGCAGGUGACGGGCAACCUCGCUGGCCAUUCCGCGGAAAUCGAAGCGCUGACUAAAGUUGAGCCAGGCGAACUGUACAACGGCGCGAAAGUGACCAAGAUGGAAAACGACAUCAAGAAACUGUUGGGUCGUUAUGGUUACGCCUAUCCGCGCGUGCAGUCGCAGCCGGAGAUCAACGACAGCGAUAAAACCGUUAAGCUGCACGUUAACGUCGACGCAGGCAACCGUUAUUACGUGCGUAAAAUUCGCUUCGAAGGCAACGACACCUCUAAAGAUGCCGUACUGCGCCGCGAAAUGCGCCAGAUGGAAGGCGCAUGGCUGGGCAGCGACCUCGUCGAUCAGGGUAAAGACCGUCUCAAUCGUUUAGGUUUCUUUGAAACGGUGGAUACUGAUACCCAGCGCGUGCCGGGCAGCCCGGACCAGGUCGACGUUGUCUACAAGGUGAAAGAGCGUAACACCGGUAGCUUCAACUUCGGUAUCGGCUACGGCACCGAGAGCGGCGUCAGCUUCCAGGCGGGCGUUCAGCAGGAUAACUGGUUAGGUACUGGCUAUGCUGUCGGGAUCAACGGUACCAAAAACGACUACCAGACCUAUACCGAGCUGUCGGUGACCAACCCGUACUUCACCGUAGACGGUGUAAGCCUCGGCGGUCGUGUCUUCUAUAAUGACUUUGAUGCGAACGAUGCGGAUCUGUCUGACUAUACCAACAAAAGCUAUGGUACAGACAUUACGCUGGGCUUCCCGGUCAACGAAUACAACACGCUGCGCGCCGGCGUCGGUUAUGUGCAUAACUCCCUGUCCAAUAUGCAGCCGCAGGUGGCAAUGUGGCGUUACCUUAACUCGAUGGGCCAGUAUCCGGACAACACCAACGACCGGAACUCGUUCAGUGCGAAUGACUUCACCUUCAACUACGGUUGGACCUAUAACAAGCUUGACCGCGGCUUCUUCCCAACGGAAGGUUCGCGCGUCAACCUGAACGGUAAGGUGACCAUUCCGGGCUCAGACAACGAGUACUACAAAGCGACGCUGGAUACCGCGACCUACGUGCCGAUCGACAACGAUCAUCAGUGGGUAGUACUGGGUCGUACGCGCUUUGGUUAUGGCGAUGGUAUCGGCGGCAAAGAGAUGCCGUUCUAUGAGAACUUCUAUGCCGGUGGUUCCAGCACCGUGCGUGGCUUCCAGUCGAACACCAUUGGUCCGAAGGCGGUGUACUUCCCGGCAAGCAGUCGUCAUGAUGAUGACGAUAGUUACGAUAAUGAAUGUAAGAGCACCGAAUCCGCACCGUGUAAAUCCGAUGAUGCGGUGGGCGGUAACGCGAUGGCGGUGGCCAGCCUUGAGCUGAUUACCCCGACGCCGUUUAUUAGUGACAAAUAUGCGAACUCGGUCCGUACUUCCGUCUUCUGGGAUAUGGGUACCGUAUGGGAUACUCACUGGGAUUCGAGCGCGUACGCUGGUUAUCCGGAUUACAGCGAUCCGAGCAACAUCCGUAUGUCUGCGGGUAUUGCCGUGCAGUGGAUGUCGCCGUUGGGGCCGUUGGUCUUCUCCUACGCCCAACCGUUCAAAAAGUACGAUGGAGACAAAGCCGAACAGUUCCAGUUUAACAUUGGUAAAACCUGGUAA SEQ ID NO: 87AUGACAGAUGUGACUAUUAAAGCGCUGGCCUCAGAGAUUCAGACCUCUGUGGAUCGCCUGAUACAGCAAUUUGCUGACGCAGGCAUCCGCAAAUCGGCUGAUGAUUCUGUGACCUCGCAAGAGAAACAAACUUUGUUGACGCACCUGAACCGUGAACACGGCUCGGCGCCAGACAAGCUGACGUUACAGCGUAAGACGCGCAGUACGUUAAAUAUUCCAGGUACCGGUGGAAAGAGUAAAUCGGUACAAAUCGAAGUCCGCAAGAAACGCACCUUUGUGAAACGCGAUCCGCAAGAGGCUGAACGCCUGGCCGCGGAAGAGCAGGCGCAGCGUGAAGCGGAAGAGCAGGCCCGUCGUGAAGCUGAAGAAGCAGCGAAACGCGAGGCGCAAUUAAAAGCUGAACGUGAGGCCGCAGAACAAGCUAAACGUGAAGUCGCUGAUAAAGCGAAACGUGAAGCUGCGGAAAAAGACAAAGUGAGCAAUCAACAUACCGACGAAAUGACCAAAACCGCCCAGGCUGAAAAGAUCCGUCGCGAGAACGAAGCCGCGGAAUUGAAGCGCAAAUCGGAAGAAGAAGCACGCCGCAAACUUGAAGAAGAAGCGCGCCGUGUAGCGGAAGAAGCACGCCGUAUGGCUGAAGAAAACGAAAAAAAUUGGUCUGAAACCUCAGACAGCCCGGAAGAUAGCAGCGACUAUCACGUCACCACAUCACAGCAUGCUCGUCAGGCUGAAGAUGAUAACGAUCGUGAAGUCGAAGGCGGUCGCGGCCGUAGCCGUAGCAGCAAAGCGGCUCGUCCGGCGAAGAAAGGCAACAAACACGCUGAAUCGAAAGCUGAUCGUGAAGAAGCCCGCGCGGCCGUGCGCGGCGGUAAAGGCGGUAAGCACCGUAAAGGUUCCGCUCUGCAGCAGGGCUUCCAGAAGCCAGCGCAGGCCGUUAACCGUGACGUCGUAAUCGGCGAAACCAUCACCGUUGGCGAACUGGCUAACAAGAUGGCGGUGAAAGGUUCUCAGGUCAUCAAAGCGAUGAUGAAGCUGGGCGCCAUGGCGACCAUCAACCAGGUCAUCGACCAGGAAACCGCACAGCUGGUUGCCGAAGAGAUGGGCCACAAAGUUAUCCUGCGUCGUGAAAACGAACUGGAAGAAGCCGUAAUGAGCGACCGUGACACCGGCGCGGCGGCUGAACCGCGCGCACCGGUCGUGACCAUUAUGGGUCACGUUGACCACGGUAAAACCUCGCUGCUGGACUACAUUCGUUCUACCAAGGUUGCCUCCGGCGAAGCGGGUGGUAUUACCCAGCACAUCGGUGCUUACCACGUCGAAACCGACAACGGCAUGAUCACCUUCCUGGAUACCCCGGGCCACGCCGCGUUUACCUCCAUGCGUGCUCGUGGCGCGCAGGCGACGGAUAUCGUGGUUCUGGUGGUGGCGGCAGACGACGGCGUGAUGCCGCAGACUAUCGAAGCUAUCCAGCACGCUAAAGCGGCGCAGGUACCGGUGGUAGUGGCGGUGAACAAGAUCGAUAAGCCAGAAGCCGAUCCGGAUCGCGUGAAGAACGAACUGUCCCAGUACGGCAUCCUGCCGGAAGAGUGGGGCGGCGAGAGCCAGUUCGUCCACGUUUCCGCGAAAGCGGGUACCGGCAUCGACGACCUGCUGGACGCGAUCCUGCUGCAGGCUGAAGUUCUUGAGCUGAAAGCGGUCCGCAACGGUAUGGCGAGCGGCGCGGUCAUCGAAUCCUUCCUUGAUAAAGGUCGUGGUCCGGUAGCUACCGUUCUGGUUCGCGAAGGUACUCUGCACAAGGGCGACAUUGUUCUGUGCGGCUUCGAAUAUGGCCGUGUGCGCGCGAUGCGUGACGAACUGGGUCGCGAAGUGCUGGAAGCGGGUCCGUCCAUUCCGGUGGAAAUCCUCGGCCUGUCCGGUGUGCCGGCUGCCGGUGAUGAAGUGACCGUAGUGCGUGACGAGAAAAAAGCGCGUGAAGUGGCGCUGUAUCGUCAGGGCAAAUUCCGUGAAGUUAAGCUGGCGCGUCAGCAGAAAUCUAAACUGGAAAACAUGUUCGCUAACAUGACCGAAGGCGAAGUUCACGAAGUGAACAUCGUACUGAAAGCGGACGUACAGGGUUCUGUCGAAGCGAUUUCCGAUUCCUUACUGAAACUGUCUACCGACGAAGUGAAAGUGAAGAUCAUCGGUUCCGGCGUAGGUGGUAUCACCGAAACCGACGCUACCCUGGCAGCAGCAUCCAACGCGAUUCUGGUUGGCUUCAACGUUCGUGCCGAUGCCUCUGCGCGUAAAGUUAUCGAAGCGGAAAGCCUGGAUCUGCGUUACUACUCCGUCAUCUAUAACCUGAUCGACGAAGUGAAAGCGGCGAUGAGCGGCAUGCUGUCUCCGGAACUGAAACAGCAGAUCAUCGGUCUGGCUGAAGUGCGUGAUGUCUUCAAAUCGCCGAAAUUCGGCGCCAUCGCGGGCUGUAUGGUUACCGAAGGGACGAUCAAACGUCACAACCCAAUCCGCGUUCUGCGUGACAACGUGGUUAUCUAUGAAGGCGAGCUGGAAUCCCUGCGCCGCUUCAAAGAUGACGUUAACGAAGUCCGUAACGGCAUGGAAUGUGGUAUCGGCGUGAAGAACUACAACGACGUUCGCGUUGGCGAUAUGAUCGAAGUGUUCGAAAUCAUCGAAAUCCAGCGUAGCAUCGAUUAA SEQ ID NO: 88AUGAAAAGAAUGUUAAUCAACGCAACUCAGCAGGAAGAGUUGCGCGUCGCCCUUGUUGAUGGGCAGCGCCUGUACGACCUGGAUAUCGAAAGCCCCGGGCACGAACAGAAAAAAGCGAACAUCUACAAAGGCAAAAUCACCCGCAUUGAACCCAGCCUUGAAGCCGCGUUUGUUGAUUACGGCGCCGAGCGUCAUGGUUUCCUCCCCCUCAAAGAAAUCGCCCGCGAAUACUUCCCCGCCAACUACAAUGCGCAUGGUCGUCCUAAUAUCAAAGACGUACUGCGGGAAGGUCAGGAAGUUAUCGUGCAGAUUGAUAAAGAAGAACGCGGCAACAAAGGCGCUGCGCUCACCACCUUUAUCAGCCUCGCGGGCAGCUAUCUGGUACUGAUGCCGAACAACCCGCGCGCCGGGGGAAUUUCCCGCCGUAUCGAGGGCGACGACCGUACCGAACUGAAAGAAGCGCUGGCGAGCCUGGAGCUUCCGGACGGCAUGGGCCUGAUCGUUCGCACCGCUGGCGUCGGCAAAUCCGCCGAAGCCCUGCAGUGGGACCUGAGCUUCCGCCUGAAGCACUGGGAAGCGAUUCAGAAAGCCGCGGAAAGCCGUCCGGCGCCGUUCCUGAUCCACCAGGAAAGCAACGUCAUUGUCCGCGCCUUCCGUGACUACCUGCGCCAGGACAUCGGCGAAAUCCUGAUCGAUAACCCGAAAGUGCUUGAGCUGGCGCGCCAGCAUAUCGCCGCGCUGGGUCGUCCGGAUUUCAGCAGCAAAAUAAAACUGUACACCGGUGAAAUCCCGCUGUUCAGCCAUUAUCAGAUCGAAUCGCAAAUUGAGUCCGCCUUCCAGCGCGAAGUGCGCCUGCCUUCCGGCGGGUCUAUCGUUAUCGAUAGCACCGAAGCGCUGACCGCGAUCGAUAUCAACUCCGCCCGCGCCACCCGCGGCGGCGAUAUCGAAGAGACAGCCUUCAAUACCAACCUCGAAGCGGCUGACGAAAUUGCCCGCCAGCUGCGUCUGCGCGACCUCGGCGGCCUGAUCGUUAUCGACUUCAUCGAUAUGACCCCGGUUCGCCACCAGCGCGCCGUGGAGAAUCGUCUGCGCGAAGCCGUCCGUCAGGACCGUGCGCGCAUUCAGAUCAGCCAUAUUUCGCGCUUCGGCCUGCUGGAGAUGUCCCGUCAGCGCCUGAGCCCGUCGCUGGGCGAGUCCAGCCACCACGUCUGCCCGCGCUGCUCCGGCACCGGCACCGUGCGUGAUAACGAAUCGCUGUCGCUCUCUAUUCUGCGUCUGAUCGAAGAAGAAGCGCUGAAAGAGAAUACCAAAGAAGUCCACGCCAUUGUUCCGGUACCGAUCGCCUCCUAUCUGCUGAACGAAAAACGUGCCGCAGUGAGCGCUAUCGAAUCCCGUCAGGGCGAUGUGCGCGUUAUUAUCGUGCCAAACGACGAAAUGCAAACGCCGCACUACUCCGUCCUGCGCGUGCGCAAAGGUGAAGAAACCUCAACGCUGAGCUAUCUGCUGCCGAAGCUGCAUGAAGAAGAAAUGGCGCUGCCAGGCGACGAUGAGCCGGCGGAGCGGAAACGUCCGGAACAGCCGGCCCUGGCCGCUUUUGUCAUGCCAGAUGCGCCGCCAGCCCCGAUGCUCGAAGAGCCUGCCGCCGCGCCUGUCGCCGCAGCGGCACCGGUCGCGGCCGCCGCACCGGCGCAGCCUGGCCUGCUCUCACGCUUCUUCAGCGCGCUGAAGAAUAUCUUCUCUGGCGCCGAAGAGGCCAAACCGGCUGAAGUUCAGGUCGAGAAGAAAGCGGAAGAAAAACCGGAGCGUCAGCAGGAGCGUCGUAAACCGCGCGCCAACAACCGCCGCGACCGCAACGACCGCCGUGAUAACCGCGACAAUCGUGACAACCGCGAUAACCGUGACAAUCGCGACACCCGUGCGGACAAUGCCGAGGGCCGUGAACCGCGCGAAUCGCGUGAAGAGAACCGUCGCAACCGUCGCGAGAAGCCGUCGCAGAACGUGGAAGCCCGUGAUGUUCGCCAAACCUCAGGCGACGACGCGGAGAAAGCGAAAUCCCGUGACGAGCAGCAGCCGCGCCGCGAACGCACCCGCCGCCGCAGUGACGACAAACGUCAGGCGCAGCAGGAAGCCAAAGCGCAGACUCGCGAAGAGCCGGUUGUGCAGGAGACGGAGCAGGAAGAGCGUGUACAAACUCUGCCGCGUCGUAAACCGCGCCAGCUGGCACAGAAAGUGCGCGUUGAGUCCGCUGUCGUCGAGCCAGUUGCCGAGAUCGUGCCAGAAGCCGUAGUGGCUGAAGUUAUCGCUCCGCACAGCGAGCCGGUGAAAGCCGAGCUGCCGGCAGGGGUGGAGAGCGUGGCGGACCAGGACGAAAAUGGCGAAUCCCGUGAAGCGAACGGUAUGCCGCGUCGCUCACGUCGCUCCCCGCGUCACCUGCGCGUCAGCGGUCAGCGUCGUCGUCGCUAUCGUGACGAACGCUAUCCGACCCAGUCGCCUAUGCCGCUGACCGUAGCCUGCGCAUCGCCGGAGAUGGCUUCCGGUAAAGUCUGGAUCCGCUACCCGGUGGUUCGUCCGCAGGAUCAGCAGCCGGAAGAGGUUCAGGUUCAGGACGCCAGCGUCGCGAAAACUGUCGAGGCCGUAGCGGCCCCGGUCGCCGUCGUUGAAACCGUUACCGCUGCGCCGGUCACCGUCGAGCCGGCUACCAUGGAACCAGUAACCGCUGAGCCGGUAGUCGUCGAGCCGGUAGCGGCCGCCGAGCCGCUGGUCGUUGAUGCUGCGGAAGUUGUCGCGCCAGCAGCCGUCGAGCCAGCGCCUCAGGAGCCGGUCACCGAAGCACCGGCUGUCGAAGCGCCUCAGGCUAUCGCGCCAGUGACGCUCGACGCCGAGCCGGUGGUGGUAGAACCUGAAGCGGUGGAAACGACGCCUGUCGUUGCAGCGCCAGUGGAAACUAUCGCCCCGGUCGCAGAAACCGUGGAGCAAGCGCCAGUGACCGAAGCGGCCCCUGCCGAACCGGUCAAAGCCGAGCCCCCGGUGAGCAAGCCGGUCGUAGUGGCGGGUCAUCGCCAUGCCACCGCGCCAAUGACCCGUGCGCCAGCUCCGGACUAUGUCCCGGAAGCACCGCGUCAUAGCACCUGGGUGCGCCCGCCGUUCGCCUUUGAAGGUAAAGGCGCCGCCGGUGGUCAUAGCGCGACCCAUAAAGCCACCGCUGAACCGACUCGCCCACAGCCCGUCGAGUAA SEQ ID NO: 89AUGCGCAAGCUCUCACUAAGUUUACUCACGCUGUCCCUCGGCGUUGCGCUGCUGCCGUUAGCGCAGGCGGCGACGACGCCUGCCCAGGAGCAUCUGCUGGAGCAGGUCCGCCUCGGCGAGGCCAGCAAUCGUGAAGACCUGGUGCGCCAGUCGCUGUACCGUCUGGAGCUGAUUGAUCCCAACAACCCGGAGCUGAUUGCCGCGCGGAUGCGCUAUCUGCUGCGUCAGGGGGAUGCCGCCGGGGCGCAAAAAGAGCUGGAACGACUGACGAAGCAGGCGCCGGACUCCCCGGAGCUGAAGGCGUCGCGCAAUGAGAUGAAAAGCAACACCGGCGAGGGCCGCCAGGCGCUGCAGCAGGCGCGACUGCUGGGCGUGGCCGGGAAGGUCGAUGAAGCCAUCGCCGCCUAUGAAAAACUGUACGGCGGGGUGCCGGAUGACGUUGACGUCGCCAUUGAGUACUGGACGCUGGUGGCGCGCCUGCCGGCCCGCCAUAGCGAAGGCGUCAGCCAGUUGAAAAAACUGAACGCCAGCGCGCCGGGCAACGUCAGCCUGCUGACUUCGCUGGCGAAGCAGAUGUUCGCCGAUAACAAACCGCAGGAGGGGUUCGCCUAUCUGGCGGAGAUGGCCCGAUCGGCCUCGGGACGCGGUAUCGCCGCCGAUAUGUGGUUCAGUGAGGUGAAAAGCAUGCCGGUGAGUAAGGCCAGCGUGCAGGCGUUGCAGCAAUUUCUUCUGCAGUUUCCCACCGGCUCGGUGGCGGCGAACGCCCGCGUUCUGCUCGACCAACAGCAGGCGCAGCUGCAGGAUCCGACUUUCCGCGCCCGCUCGGAAGGGCUGGCGGCGGUCAAGUCCGGGAAUACCACGCAGGCGGUCGCGGAUCUGCAGAAAGCCGUUCAGGCCGACAGCCGCGACAGCGACGCGGUGGGCGCUCUCGGCCAGGCCUAUUCCCAGCGCGGCGACCGCGCGCGGGCAGUGGCGCAGCUCAGUAAAGCGAUUGCUAUGGACCCUGACAGCCCGAACCGCGGCAAGUGGGACAGCCUGCUGCAAACUAACCGCUACUGGCUGCUGAUAAAGCAGGGGGAUAACGCCCUGAAAGCCGGCCAGCUUUCGCAGGCGCAGAACUAUUAUGCCCAGGCGCAGCGGGUCGAUCGCACCGACAGCUAUGCCGUGCUGGGGCUGGGGGACGUCGCGGCGGCGCGCAAAGAGGCGGCGGCGGCGGAGCGCUAUUACCAGCAGGCGUUGCGCCUGGAUCGCGGCAAUAACCUGGCGGUGCGCGGCCUGGCCAACCUCUAUCGCGCCGAAUCGCCGGAGAAAGCCAGCGCCUGGAUCGCCGGCCUCCCUCCCGCUCAGCGGCGGAGCAUCGAUGAUAUUGAGCGCAGCCUGACUAACGACCGGCUGGAGAAACAGGCGCAGGCUCUGGAGAGCCAGGGCAACUGGGCGCAGGCGGCGGAAGUUCAGCGUCGGCGCCUGGCGCUGGAUCCGGACAGCGUCUGGAUAACCUACCGUCUGGCGCGGGAUCUGGUCAGCGCCGGCGAACGCCAGGAGGCCGACGCGCUGAUGCGGACGAUGGUCAACCGCCAGCCGCAGGACGCCGAACGGGUCUACGCCUCGGGACUCUACCUGUCGGGGAACGACCAGGACGAUCUGGCUCUGGCGCAAAUCGCCGCUCUGCCGCGCAGCGCGUGGACGGAUAACAUUCGUGAGCUCGAAGCGCGUUUGCAAAGCGACCGGGUGCUGCGCCAGGCCAACCAGCUGCGCGACAGCGGUAACGAAGCGCAGGCGAUCGCCCUUAUCCGACAGCAGCCCGCCUCGGUGCGCUAUGACCUGACGCUCGCCGACUGGGCGCAGCAGCGCGGCGACAGCCAGACGGCGAUUGCCAACUAUCAGCGGGUGCUGCGCCAGGAGGCCGACAACGGCGAUGCGCGCCUCGGCCUUGCGGAAGUCUACCUGGCCGAGGGCGAUAAACCGGCCGCCCGGGCGCAGGUCAUGCAGCUGAAAGGCGCAGAGACCGAAUCCAUGAACAUGCAGCGGCGGGUGGCGCUGGCGCGAGCUGGCCUUGGCGAUACCGCUGACGCGCAACGGAUUUUUAAUCAGAUUGUGCCGCAGGCGAAGGCGCAGCCGCCCUCGAUGGAGAGCGCGCUGGUGCUGCGCGAUGCCGCGCGCUUUGCCACCCAGAGCGGGGCGCCGCAGCAGGCGCUGACGCACUACCGGGAAGCUAUGGUGGCCUCCGGCAUUACCCCCGCGCAGCCGCAGGAUAACGAUACUUUUACGCGGCUGACGCGCAACGACAGCCAUGAUGACUGGCUGAAGCGCGGGAUCCGCAGCGAUGCCGCCGACCUUUAUCGUCAGCAGGAUCUGAACGUCACCCUGGAACAUGACUUCUGGGGUUCCAGCGGCACCGGCGGCUAUUCCGACCUGAAGGCGCAUACCACCAUGCUGCAGAUGGAUGCUCCGCUGGCGGAUGGCCGGAUGUUCUUCCGCACCGACCUGGUCAAUAUGGAUGCCGGCAGCUUUUCCACCCACAGCGACGGGAGCUACUCGCCCAGCUGGGGCACCUGCGGGGAGAUCGCCUGUACCAGCGGCAGUAAAAAUCAGACCGACAGCGGGGCCAGCGUGGCGGUCGGCUGGAAGAAUGACACCUGGAGCGGGGAUAUCGGCACCACGCCGAUGGGCUUCAAUGUCGUCGAUGUGGUGGGGGGGCUGAGCUACAGCAGCGACGUCGGGCCGGUGGGGUACACGGUCAACGUCCACCGGCGGCCUAUCUCCAGCUCGCUGCUCUCCUUUGGCGGGCAGAAGGACAGCAGCAGCCAUACCGGCGCCACCUGGGGCGGCGUCCGCGCCGACGGCGGCGGCCUGAGCCUGAGCUACGAUCGCGGGGAGGCUCACGGCAUCUGGUCCUCGCUGGGCGCCGACUCGCUGACCGGUAAAAACGUGGCGGAUAACUGGCGCGUGCGCUGGAUGACCGGGUACUACUACAAGGUCAUCAACGAGAAUAAUCGUCGCGUCACCGUCGGCCUCAACAAUAUGAUCUGGCACUACGACAAAGAUCUCAGCGGCUACACCCUCGGCCAGGGCGGCUAUUACAGCCCACAGGAGUAUCUCUCGUUCGCCGUGCCGGUGACCUGGCGUCAGCGCACCGAGAACUGGUCCUGGGAGCUCGGCGGGUCGGUGUCAUGGUCCCAUUCGCGCACCCAGACGCAAGCCCGCUAUCCGCUGCUGAACCUGAUCCCGUCCGACUACCGGCAGCGCGCCAGCGAGCUGACGGAGGAGGGGAGCAGCAGCCAUGGAUUCGGUUACACCGCCAGAGCGCUGGUGGAGCGGCGGGUGACCAGCAACUGGUUCGUCGGCGCCGCGGUCGAUAUUCAGCAGGCGAAGGAUUACACCCCGAGCCAUGCGCUGCUUUACGUCCGCUACUCGGCGGCCGGCUGGCAGGGGGAUCUGGAUAUGCCGCCCCAGCCGCUGGUGCCCUACGCCGACUGGUAG SEQ ID NO: 90AUGAGCCAGGAAUACACCGAAGACAAAGAAGUCAAACUAACCAAACUCAGCAGCGGGCGCCGACUCCUUGAGGCGAUGCUCAUCCUUUGCUCCCUCUUCGCCAUCUGGCUGAUGGCGGCACUACUGAGCUUUAACCCCUCGGACCCCAGCUGGUCGCAAACGGCAUGGCAUGAGCCUAUUCAUAAUUUAGGCGGCGCCCCCGGCGCGUGGCUUGCCGAUACCCUCUUUUUCAUUUUUGGCGUCAUGGCCUACACCAUCCCGGUGAUCAUCAUCGGCGGAUGCUGGUUUGCCUGGCGGCAUCAGGAAAACGACGAAUACAUUGAUUAUUUUGCCGUUUCCCUUCGCCUCAUCGGUGCGUUAGCCCUGAUCCUGACCUCCUGUGGUCUGGCGGCGAUUAACGCCGAUGAUAUCUGGUACUUCGCCUCCGGCGGGGUGAUCGGCAGCCUGCUGAGCACCACGCUGCAACCCCUGCUGCACAGCAGCGGCGGCACCAUCGCCCUGUUGUGUAUCUGGGCGGCCGGGCUGACGCUGUUCACCGGCUGGUCGUGGGUCAGCAUUGCGGAAAAGCUGGGCGGCGGCAUCCUGUCCGUUCUCACCUUUGCCAGCAACCGUACCCGUCGGGAUGAUACCUGGGUCGAUGAAGGCGAAUAUGAAGACGACGAGGAAGAGUACGACGACGAAGAGGCGGCCAGGCCGCAGGAAUCGCGUCGCGCCCGUAUCUUACGCAGCGCGCUGGCGCGGCGUAAGCGUCUGGCCGAGAAGUUUACCAACCCUAUGGGGCGUAAAACCGACGCUGCGCUUUUCUCCGGCAAACGGAUGGAUGACGGCGAAGAGGUGGUGCAAUACAGCGCCAGCGGGGCGCCUGUUGCCGCCGACGAUGUACUGUUUUCCGGCGCCAGCGCCGCGCGUCCCGCAGAGGAUGAUGUGCUGUUCUCCGGCGCCAGCGCCGUGCGCCCGGGCGAUUUCGACCCUUACGAUCCGUUGUUGAAUGGCCACAGUAUCGCUGAGCCGGUAAGCGCAGCGGCGGCGGCUACAGCCGCGCCGCAGGCGUGGGCAGAAUCACCGGUGGGCCAUCACGGCGCUGCGCCAGCUUAUCAGCCGGAAGCCAGCUAUCCGCCGCAGCAGGCCUAUCAGCCUGAACCCGCUCCGUUCCAGCAGGCCUAUCAGCCUGAACCCGCUCCGUUCCAGCAGGCUGCUUAUCAGCCGCCAGCGGGGCAAACCGCACCGCAGGCGUAUCAGCCUGAGCCAGCGCCGUAUCAACAGCCGGUUUACGAUCCGCGUGCCGGUCAACCUGCGCCGCAGGCCUAUCAGCCUGAGCCAGCGCCGUAUCAGCAGCCGGCUUACGAUCCGUAUGCCGGUCAACCUGCGCCGCAGGCCUAUCAGCCUGAACCUGCGCCGUAUCAGCAGCCGGCUUACGAUCCGCAUGCCGGUCAACCUGCACCGCAGGCCUAUCAGCCUGAGCCAGCGCCGUAUCAGCAGCCGGCUUACGAUCCCUAUGCCGGUCAACCUGCGCCGCAGGCCUAUCAGCCGGAGCCAGCGCCGUAUCAGCAGCCAACUUACGAUCCCUAUGCCGGUCAGCCUGCGCCUCAGACCUAUCAGCAGCCGGCUUACGAUCCGAAUGCCGGUCAGCCCGCGCCGCAGCCGUAUCAGCCGGAGCCAGCGGCGUAUCAGCCGCAAAGCGCGCCAGUUCCCCCACCGGAGCCAGAGCCCGAGGUCGUGCAGGAGGAAGUGAAACGUCCGCCGCUCUAUUAUUUCGAGGAAGUGGAAGAGAAGCGGGCGCGCGAACGCGAGCUGUUGGCCUCCUGGUAUCAGCCAAUUCCUGAGCCGGAAAGUCCGAUUGCCACUAAACCGCUGACGCCGCCGACCACUGCGUCCAAACCGCCAGUGGAGACAACCGUAGUCUCUGCGGUAGCGGCUGGGGUGCAUCAGGCUACCGCCGCCAGCGGCGGCGCGGCGGCAGCAACCUCGUCCACUGCCGCAUCCGCUGCGGCUACGCCAUUGUUCAGCCCGGCGUCCAGCGGCCCAAGGGUUCAGGUGAAAGAGGGCAUCGGUCCAAAACUACCGCGGCCCAAUCGCGUGCGUGUUCCUACGCGUCGGGAACUGGCCUCCUACGGCAUCAAGCUACCGUCGCAGCGGGAGGCGGAACAGCGCGCGCGGCAGGCGGAGCGCGAUCCGCAUUAUGAUGAUGAGCUGCUCUCGGAUGAGGAAGCGGAUGCUAUGGAGCAGGAUGAACUGGCUCGCCAGUUCGCCGCCACCCAGCAGCAGCGCUACGGUCAUCGCUGGGAAGACGAUAACGCGACUGAUGACGAUGAGGCCGACGCCGCGGCGGAAGCGGAGCUGGCGCGUCAGUUUGCCGCUACCCAGCAGCAGCGGUACGCUACCGAGCAGCCGCCGGGCGCCAACCCGUUCUCGCCGGCAGAUUAUGAAUUCUCGCCGAUGAAAACGUUGGUCAAUGACGGCCCGAGCGAACCGCUGUUUACGCCGACGCCGGAAGUCCAGCCGCAGCAGCCGGCCCAGCGCUAUCAACAACCGGCGGCCGCUCCGCAGCAGGGUUAUCAACCUGCGCAGCAUCAGCCGAUACACCAUCAGCCUGUGCCGCCACAGCCGCAGUCCUAUCCGACUGCGUCGCAGCCCGUACAGCCGCAACAACCGGUUGCCCCGCAGGGGCAUCAGCCUGCCGCCCCUGCGCCGCAGGAGAGCCUGAUCCACCCGCUGCUGAUGCGCAAUGGCGAUAGUCGACCGCUGCAAAAGCCGACCACGCCACUGCCGUCGCUGGAUCUGCUUACCCCGCCGCCGAGUGAAGUCGAGCCGGUGGAUACCUUUGCUCUCGAGCAGAUGGCACGCCUGGUGGAAGCGCGACUCGCUGAUUUCCGCAUUAAAGCGGAUGUGGUGAACUACUCACCGGGGCCGGUGAUCACCCGCUUCGAACUGAAUCUGGCGCCUGGCGUUAAGGCCGCACGGAUCUCUAACCUGUCACGGGACCUGGCGCGAUCGCUGUCAACGGUCGCCGUGCGCGUGGUGGAGGUGAUCCCGGGCAAACCGUAUGUCGGGCUUGAGCUGCCGAAUAAAAAACGCCAGACCGUCUACCUGCGUGAAGUGCUCGACAACGCCAAGUUCCGUGAUAACCCAUCUCCGCUCACCGUGGUGUUGGGUAAAGACAUCGCUGGCGAUCCGGUAGUAGCCGAUCUGGCGAAAAUGCCGCAUCUGCUGGUGGCCGGUACCACCGGUUCCGGUAAGUCUGUUGGCGUCAACGCCAUGAUCCUCAGCAUGCUCUACAAGGCGCAGCCGGAAGAUGUGCGUUUCAUUAUGAUCGACCCGAAAAUGCUCGAGCUGUCGGUCUACGAAGGAAUUCCGCACCUGCUGACGGAAGUGGUCACCGACAUGAAAGACGCCGCCAAUGCGCUGCGCUGGAGCGUCAAUGAGAUGGAGCGCCGCUACAAGCUGAUGUCGGCGCUGGGCGUGCGUAACCUCGCGGGCUACAACGAGAAGAUCGCCGAAGCCGCGCGCAUGGGACGUCCGAUCCCGGAUCCGUACUGGAAGCCUGGCGACAGCAUGGACGCCGUACAUCCGGUGCUGGAAAAACUGCCGUACAUCGUGGUGCUGGUGGAUGAAUUCGCCGAUCUGAUGAUGACCGUCGGCAAAAAGGUGGAAGAGCUGAUCGCUCGCCUGGCGCAGAAAGCGCGCGCGGCGGGGAUCCACCUGGUGCUGGCGACACAGCGUCCGUCGGUAGAUGUUAUUACCGGCCUGAUUAAGGCCAACAUCCCGACGCGCAUCGCCUUUACCGUGUCGAGUAAAAUUGACUCACGUACCAUUCUCGAUCAGGGCGGCGCGGAAUCGCUGCUGGGUAUGGGGGAUAUGCUUUACUCCGGGCCGAACUCUACCACGCCGGUGCGUGUCCACGGGGCGUUUGUGCGCGACCAGGAAGUCCACGCCGUGGUUCAGGACUGGAAAGCCCGCGGUCGCCCGCAAUAUGUGGAUGGCAUUACCUCCGACAGCGAAAGCGAAGGCGGCGGUGGCGGCUUCGACGGCGGGGAAGAGUUGGAUCCGUUGUUCGAUCAGGCAGUCAACUUUGUGACCGAGAAGCGCAAAGCGUCGAUUUCCGGGGUUCAGCGUCAGUUCCGCAUCGGCUAUAACCGUGCCGCGCGUAUUAUCGAACAGAUGGAAGCGCAGGGUAUCGUCAGCGAGCAGGGCCAUAACGGUAACCGCGAAGUGCUGGCGCCGCCGCCCUUUGAAUGA

The polypeptides of the invention can also be designated as follows:

SEQ ID NO: Designation 1 KP1_2999 2 KP1_0355 3 KP1_3995 4 KP1_3023 5KP1_1709 6 KP1_4823 7 KP1_1443 8 KP1_1444 9 KP1_0026 10 KP1_3952 11KP1_0090 12 KP1_4374 13 KP1_1620 14 KP1_5089 15 KP1_1701 16 KP1_1186 17KP1_0947 18 KP1_1632 19 KP1_1274 20 KP1_3820 21 KP1_0953 22 KP1_2972 23KP1_0306 24 KP1_2284 25 KP1_4356 26 KP1_1032 27 KP1_4886 28 KP1_2074 29KP1_5221 30 KP1_1891 91 KP1_1547 92 KP1_1958 93 KP1_4144 94 KP1_4102

When designating a fragment of one of these proteins, this is done usingthe nomenclature KP1_XXXX-A-p1-p2, where XXXX is any of the 4 digitnumbers following “KP1” in the table above, and p1 and p2 are the startand end amino acids relative to the entire sequence of the protein. Forinstance KP1_1891-50-200 is the fragment of KP1_1891 that has the aminoacid sequence defined by residues 50 to 200 of KP1_1891, i.e. a(poly)peptide having the amino acid sequence of SEQ ID NO: 30, residues50-200.

EXAMPLE

Challenge Studies in Mice

1. Challenge Study (Klebsiella pneumonia—Intranasal (IN) Model):

-   -   Challenge strain: Klebsiella pneumoniae NTUH-K2044 (Wu K M et        al. (2009), J. Bacteriol, 191:4492-4501).    -   Mouse strain: BalbC/ByJ (inbred)    -   Dose: 25 μg in each immunization.    -   Immunization route: 3× subcutaneous    -   Immunization interval: 14 days    -   Inoculation route: intranasal (IN)    -   End point: Lethal challenge    -   Adjuvant choice: Priming immunization used Alum+IFA (incomplete        Freund's adjuvant); 1^(st) and 2^(nd) booster immunizations used        alum only    -   Bleeds: Bleed mouse 4 days before challenge for subsequent ELISA        test.    -   Trial type: Double blinded    -   No of mice per group: At most 16 mice (see tables 1-6 for        details)    -   Monitoring period: 7 days

2. Challenge Study (Klebsiella pneumonia—Intraperitoneal (IP Model)):

-   -   Challenge strain: Klebsiella pneumoniae NTUH-K2044)    -   Mouse strain: NMRI (outbred)    -   Dose: 25 μg in each immunization.    -   Immunization route: 3× subcutaneous    -   Immunization interval: 14 days    -   Inoculation route: intraperitoneal (IP)    -   End point: Lethal challenge    -   Adjuvant choice: Priming immunization used Alum+IFA (incomplete        Freund's adjuvant); 1^(st) and 2^(nd) booster immunizations used        alum only    -   Bleeds: Bleed mouse 4 days before challenge for subsequent ELISA        test.    -   Trial type: Double blinded    -   No of mice per group: At most 16 mice (see tables 1-6 for        details)    -   Monitoring period: 7 days

A total 6 experiments was carried out. Only experiment 2 utilised the IPmodel whereas the remaining experiments utilised the IN model.

A number of the tested proteins proved insoluble in saline. Instead theywere solubilized in 4 M urea to avoid precipitation before addingaluminum hydroxide. After adding aluminum hydroxide the urea is removedcompletely. The remaining proteins are solubilized in physiologicalsaline.

The protocol for immunization is described below.

1^(st) immunization:

-   -   25 μg protein (per mice) are mixed with 100 μl aluminum        hydroxide (Alhydrogel 2.0%, Brenntag) per 125 μg protein and        incubated with end-over-end rotation for 1 hour.    -   The compositions is centrifuged at 1000 rpm for 2 minutes and        the supernatant is removed    -   The alu-beads are washed once (slowly) in 0.9% (0.15 M) NaCl to        remove excess urea    -   Freund's incomplete adjuvant (Sigma) is added 1:1 (v/v) and the        resulting mixture is vortexed thoroughly for 1 hour.    -   Subsequently the final composition is injected subcutaneously

2^(nd) and 3^(rd) immunization

-   -   The mice receive booster immunization with 2 weeks interval,        using the same amount of protein mixed with aluminum hydroxide        and physiological saline solution.    -   Subsequently the final composition is injected subcutaneously

The following table A lists the immunogens used in each of theimmunization studies in 6 different experiments as well as the p-valuefor the survival in each group when compared to mice vaccinated withphosphate buffered saline alone.

The corresponding survival plots are shown in FIGS. 1-6, which show theresults for Experiments 1-6, respectively. The survival data are alsoindicated for each group of mice in each experiment in Tables 1-6.

TABLE A Kaplan-Meier survival curve overview Challenge: EXPERIMENT #1P-value (IN model) Immunization agent-Protein ID(s) Log rank testFisher's exact test Group 1 vs PBS (KP1_1547-26-742; NCBI-ProteinID:BAH62300) 0.2321 0.5000 SEQ ID NO: 91, residues 26-742 Positive controlGroup 2 vs PBS (KP1_1958-22-356, NCBI-ProteinID: BAH62679) 0.9346 0.7419SEQ ID NO: 92, residues 22-356 Postive control Group 3 vs PBS(KP1_4144-1-245, NCBI-ProteinID: BAH64685) 0.0004 0.0030 SEQ ID NO: 93,residues 1-245 Postive control Group 4 vs PBS (KP1_1632-23-597 +KP1_1632-276-597 + KP1_1632-23-275) <0.0001 <0.0001 Mixture of 3peptides: SEQ ID NO: 18, residues 23-597 + SEQ ID NO: 18 residues276-597 + SEQ ID NO: 18, residues 23-275 EXPERIMENT # 2 (IP model)Protein ID Log rank test Fisher's exact test Group 1 vs PBS(KP1_5089-121-428 + KP1_0947-1-535 + KP1_0947-21-535) 0.6869 0.32700Mixture of 3 peptides: SEQ ID NO: 14, residues 121-428 + SEQ ID NO: 17,residues 1-535 + SEQ ID NO: 17, residues 21-535 Group 2 vs PBS(KP1_1620-1-382 + KP1_1620-21-382 + KP1_4374-27-376) 0.0249 0.02690Mixture of 3 peptides: SEQ ID NO: 13, residues 1-382 + SEQ ID NO: 13,residues 21-382 + SEQ ID NO: 12, residues 27-376 Group 3 vs PBS(KP1_0953-31-500 + KP_0953-31-675 + KP1_0355-22-117) 0.0153 0.01170Mixture of 3 peptides: SEQ ID NO: 21, residues 31-500 + SEQ ID NO: 21,residues 31-675 + SEQ ID NO: 2, residues 22-117. Group 4 vs PBS(KP1_4356-35-790 + KP1_4356-450-790 + KP1_4356-35-450 + 0.2216 0.02690KP1_0306-25-752 + KP1_0306-470-752 + KP1_0306-25-469) Mixture of 6peptides: SEQ ID NO: 25, residues 35-790 + SEQ ID NO: 25, residues450-790 + SEQ ID NO: 25, residues 35-450 + SEQ ID NO: 23, residues25-752 + SEQ ID NO: 23, residues 470-752 + SEQ ID NO: 23, residues25-4690 EXPERIMENT # 3 (IN model) Protein ID Log rank test Fisher'sexact test Group 1 vs PBS (KP1_5221-23-650 (NaCl) + KP1_5221-651-1159(Urea)) 0.0156 0.2759 Mixture of 2 peptides: SEQ ID NO. 29, residues23-650 (in saline) + SEQ ID NO: 29, residues 651-1159 (in Urea) Group 2vs PBS (KP1_1186-35-484 (NaCl)) 0.3488 1.0000 1 peptide: SEQ ID NO: 16,residues 25-484 Group 3 vs PBS (KP1_3995-22-119 (NaCl) + KP1_3995-22-119(Urea)) 0.8585 0.4839 Mixture of 2 peptides: SEQ ID NO: 3, residues22-119 (in saline) + SEQ ID NO: 3, residues 22-119 (in Urea) Group 4 vsPBS (KP1_1032-21-809 (Urea) + KP1_1032-451-809 (Urea) + KP1_1032-21-0.0576 0.1129 450 (NaCl)) Mixture of 3 peptides: SEQ ID NO: 26, residues21-809 (in Urea) + SEQ ID NO: 26, residues 451-809 (in Urea) + SEQ IDNO: 26, residues 21- 450 (in saline) EXPERIMENT # 4 (IN model) ProteinID Log rank test Fisher's exact test Group 1 vs PBS (KP1_1709-1-121(NaCl)) 0.2473 1.0000 1 peptide: SEQ ID NO: 5, residues 1-121 (insaline) Group 2 vs PBS (KP1_2999-22-94 (NaCl)) 0.7392 1.0000 1 peptide:SEQ ID NO: 1, residues 22-94 (in saline) Group 3 vs PBS (KP1_1274-36-624(NaCl)) 0.5190 1.0000 1 peptide: SEQ ID NO: 19, residues 36-624 (insaline) Group 4 vs PBS (KP1_0026-1-168 (NaCl)) 0.3482 1.0000 1 peptide:SEQ ID NO: 9, residues 1-168 (in saline) EXPERIMENT # 5 (IN model)Protein ID Log rank test Fisher's exact test Group 1 vs PBS(KP1_4102-582-1099 + KP1_4102-1100-1649, i.e. two fragments of 0.00120.0217 NCBI-ProteinID: BAH64645) Mixture of 2 peptides: SEQ ID NO: 94,residues 582-1099 + SEQ ID NO: 94, residues 1100-1649 Postive controlGroup 2 vs PBS (KP1_3820-26-657 + KP1_3820-392-657 + KP1_3820-26-391 +<0.0001 <0.0001 KP1_3820-26-153 + KP1_0306-61-177) Mixture of 5peptides: SEQ ID NO: 20, residues 26-657 + SEQ ID NO: 20, residues392-657 + SEQ ID NO: 20, residues 26-391 + SEQ ID NO: 20, residues26-153 + SEQ ID NO: 23, residues 61-177 Group 3 vs PBS (KP1_2284-1-761 +KP1_2284-515-761 + KP1_2284-1-514 + 0.0019 0.0217 KP1_2284-61-176)Mixture of 4 peptides: SEQ ID NO: 24, residues 1-761 + SEQ ID NO: 24,residues 515-761 + SEQ ID NO: 24, residues 1-514 + SEQ ID NO: 24,residues 61-176 Group 4 vs PBS (KP1_2972-25-701 + KP1_2972-450-696 +KP1_2972-25-449 + <0.0001 0.0088 KP1_2972-20-154) Mixture of 4 peptides:SEQ ID NO: 22, residues 25-701 + SEQ ID NO: 22, residues 450-696 + SEQID NO: 22, residues 25-449 + SEQ ID NO: 22, residues 20-154 EXPERIMENT #6 (IN model) Protein ID Log rank test Fisher's exact test Group 1 vs PBS(KP1_5089-121-428 + KP1_0947-1-535 + KP1_0947-21-535) 0.0148 0.1129Mixture of 3 peptides: SEQ D NO: 14, residues 121-428 + SEQ ID NO: 17,residues 1-535 + SEQ ID NO: 17, residues 21-535 Group 2 vs PBS(KP1_1620-1-382 + KP1_1620-21-382 + KP1_4374-27-376) 0.0006 0.0506Mixture of 3 peptides: SEQ ID NO: 13, residues 1-382 + SEQ ID NO: 13,residues 21-382 + SEQ ID NO: 12, residues 27-376 Group 3 vs PBS(KP1_0953-31-500 + KP1_0953-31-675 + KP1_0355-22-117) <0.0001 0.0004Mixture of 3 peptides: SEQ ID NO: 21, residues 31-500 + SEQ ID NO: 21,residues 31-675 + SEQ ID NO: 2, residues 22-117 Group 4 vs PBS(KP1_4356-35-790 + KP1_4356-450-790 + KP1_4356-35-450 + 0.0012 0.0004KP1_0306-25-752 + KP1_0306-470-752 + KP1_0306-25-469) Mixture of 6peptides: SEQ ID NO: 25, residues 35-790 + SEQ ID NO: 25, residues450-790 + SEQ ID NO: 25, residues 35-450 + SEQ ID NO: 23, residues25-752 + SEQ ID NO: 23, residues 470-752 + SEQ ID NO: 23, residues25-469

Table 1, Survival in Experiment 1

Group Survival Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 1 # Alive16 16 16 16 7 0 0 0 % Survival 100.0 100.0 100.0 100.0 43.8 0.0 0.0 0.02 # Alive 15 15 15 15 8 3 1 1 % Suivival 100.0 100.0 100.0 100.0 53.320.0 6.7 6.7 3 # Alive 16 16 16 16 14 12 11 9 % Survival 100.0 100.0100.0 100.0 87.5 75.0 68.8 56.3 4 # Alive 16 16 16 16 16 16 15 14 %Survival 100.0 100.0 100.0 100.0 100.0 100.0 93.8 87.5 5 # Alive 16 1616 16 7 4 1 1 % Survival 100.0 100.0 100.0 100.0 43.8 25.0 6.3 6.3

Table 2, Survival in Experiment 2

Group Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 1 # Alive 16 13 44 4 4 4 4 % Survival 100 81.3 25.0 25.0 25.0 25.0 25.0 25.0 2 # Alive 1615 9 9 9 9 8 8 % Suivival 100 94 56 56 56 56 50 50 3 # Alive 16 15 9 9 99 9 9 % Survival 100 94 56 56 56 56 56 56 4 # Alive 16 11 8 8 8 8 8 8 %Survival 100 69 50 50 50 50 50 50 5 # Alive 16 14 2 2 2 2 2 2 % Survival100 87.5 12.5 12.5 12.5 12.5 12.5 12.5

Table 3, Survival in Experiment 3

Group Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 1 # Alive 16 16 1616 10 5 3 1 % Survival 100.0 100.0 100.0 100.0 62.5 31.3 18.8 6.3 2 #Alive 15 15 15 15 7 1 0 % Suivival 100.0 100.0 100.0 100.0 46.7 6.7 0.03 # Alive 15 15 15 15 3 1 1 1 % Survival 100.0 100.0 100.0 100.0 20.06.7 6.7 6.7 4 # Alive 16 16 16 16 7 4 3 3 % Survival 100.0 100.0 100.0100.0 43.8 25.0 18.8 18.8 5 # Alive 16 16 16 16 4 1 0 0 % Survival 100.0100.0 100.0 100.0 25.0 6.3 0.0 0.0

Table 4, Survival in Experiment 4

Group Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 1 # Alive 10 10 1010 1 0 0 0 % Survival 100.0 100.0 100.0 100.0 10.0 0.0 0.0 0.0 2 # Alive15 15 15 15 6 0 0 0 % Suivival 93.8 93.8 93.8 93.8 37.5 0.0 0.0 0.0 3 #Alive 14 14 14 14 3 0 0 0 % Survival 100.0 100.0 100.0 100.0 21.4 0.00.0 0.0 4 # Alive 15 15 14 14 3 0 0 0 % Survival 100.0 100.0 93.3 93.320.0 0.0 0.0 0.0 5 # Alive 16 15 15 15 6 0 0 0 % Survival 100.0 93.893.8 93.8 37.5 0.0 0.0 0.0

Table 5, Survival in Experiment 5

Group Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 1 # Alive 16 16 1616 14 8 7 5 % Survival 100.0 100.0 100.0 100.0 87.5 50.0 43.8 31.3 2 #Alive 16 16 16 16 15 14 13 12 % Suivival 100.0 100.0 100.0 100.0 93.887.5 81.3 75.0 3 # Alive 16 16 16 16 14 8 6 5 % Survival 100.0 100.0100.0 100.0 87.5 50.0 37.5 31.3 4 # Alive 16 16 16 16 16 11 9 6 %Survival 100.0 100.0 100.0 100.0 100.0 68.8 56.3 37.5 5 # Alive 16 16 1616 8 2 0 % Survival 100.0 100.0 100.0 100.0 50.0 12.5 0.0

Table 6, Survival in Experiment 6

Group Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 1 # Alive 16 16 1615 10 7 5 3 % Survival 100.0 100.0 100.0 93.8 62.5 43.8 31.3 18.8 2 #Alive 16 16 15 15 13 9 8 4 % Suivival 100.0 100.0 93.8 93.8 81.3 56.350.0 25.0 3 # Alive 16 16 16 16 16 12 10 9 % Survival 100.0 100.0 100.0100.0 100.0 75.0 62.5 56.3 4 # Alive 16 15 15 14 13 9 9 9 % Survival100.0 93.8 93.8 87.5 81.3 56.3 56.3 56.3 5 # Alive 16 16 16 16 6 0 %Survival 100.0 100.0 100.0 100.0 37.5 0.0

1. A method for treatment or amelioration of infection with K.pneumoniae, in particular infection with multi-resistant K. pneumoniae,comprising administering to an individual in need thereof atherapeutically effective amount of a monoclonal antibody, whichspecifically binds to a polypeptide consisting of a) an amino acidsequence SEQ ID NO: 25, or b) an amino acid sequence, which is afragment of SEQ ID NO: 25 consisting of residues 35-790 or residues450-790 or residues 35-450.
 2. The method according to claim 1, whereinthe monoclonal antibody specifically binds to, residues 35-790 of SEQ IDNO:
 25. 3. The method according to claim 1, wherein the monoclonalantibody specifically binds to, residues 450-790 of SEQ ID NO:
 25. 4.The method according to claim 1, wherein the monoclonal antibodyspecifically binds to, residues 35-450 of SEQ ID NO:
 25. 5. The methodaccording to claim 1, wherein the monoclonal antibody is selected from amulti-domain antibody and a single-domain antibody of a llama or acamel.
 6. The method according to claim 5, wherein the multi-domainantibody is selected from a murine antibody, a humanized antibody, and afully human antibody.
 7. The method according to claim 1, wherein themonoclonal antibody specifically binds to SEQ ID NO:
 25. 8. A method forprophylaxis, treatment or amelioration of infection with K. pneumoniae,in particular infection with multi-resistant K. pneumoniae, comprisingadministering to an individual in need thereof a therapeuticallyeffective amount of an antibody analogue, which specifically binds to apolypeptide consisting of a) an amino acid sequence SEQ ID NO: 25, or b)an amino acid sequence, which is a fragment of SEQ ID NO: 25 consistingof residues 35-790 or residues 450-790 or residues 35-450, wherein theantibody analogue is selected from an Fab or an F(ab′)2, and an scFV. 9.The method according to claim 8, wherein the antibody analoguespecifically binds to SEQ ID NO:
 25. 10. The method according to claim8, wherein the antibody analogue specifically binds to residues 35-790of SEQ ID NO:
 25. 11. The method according to claim 8, wherein theantibody specifically binds to, residues 450-790 of SEQ ID NO:
 25. 12.The method according to claim 8, wherein the antibody specifically bindsto, residues 35-450 of SEQ ID NO: 25.